Sealed containers and methods of making and filling same

ABSTRACT

Disclosed is a uniquely configured medicament vial assembly which includes a storage vial, a stopper member and a securing ring. The vial assembly is configured to improve healthcare worker safety by providing a shielded gripping location to aid in the reduction of accidental needle sticks. The storage vial has a body portion which defines an interior chamber for storing a predetermined medicament and a neck portion through which medicament is received into and withdrawn from the interior chamber. The stopper member is inserted into the mouth of the vial and establishes a first seal. The securing ring is engaged with the mouth of the vial and adapted and configured for retaining the stopper member within the vial mouth and effectuating a second seal. The securing ring is formed from a thermoplastic and/or elastic material. Preferably, the securing ring is formed by molding the thermoplastic and/or elastic material over a portion of the storage vial and stopper member when engaged within the vial mouth.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/393,966, filed Mar. 21, 2003, entitled“Medicament Vial Having A Heat-Sealable Cap, And Apparatus and MethodFor Filling The Vial”, which is a divisional of similarly titled U.S.patent application Ser. No. 09/781,846, filed Feb. 12, 2001, now U.S.Pat. No. 6,604,561, issued Aug. 12, 2003, which, in turn, claims thebenefit of similarly titled U.S. Provisional Application Serial No.60/182,139, filed on Feb. 11, 2000, and further, this application claimspriority on U.S. Provisional Patent Application No. 60/408,068, filedSep. 3, 2002, entitled “Sealed Containers And Methods Of Making AndFilling Same”, each of which is hereby expressly incorporated byreference as part of the present disclosure.

FIELD OF THE INVENTION

[0002] The present invention relates to sealed containers, and moreparticularly, to containers, such as medicament vials, which have uniquespool-like or “diabolo” shaped configurations, and still moreparticularly, to containers that include a closure device thathermetically seals the container, that can be sterilized usingirradiation, such as laser, gamma, e-beam, x-ray or other forms ofionizing radiation, that can be needle filled when sealed to thecontainer, and that can be thermally resealed after needle filling, suchas by applying laser radiation to the needle fill hole.

BACKGROUND OF THE RELATED ART

[0003] Medicaments such as vaccines are often stored in vials prior touse. Vials typically include a main body portion that is eithercylindrical or spherical in shape and has a neck portion dependingtherefrom. The neck portion defines a mouth for receiving the medicamentinto an interior chamber defined in the vial body. Normally, the vialsare filled with medicament, and then a pre-sterilized cap or closuredevice is installed to seal the medicament within the vial.

[0004] The vial cap is typically a two-piece assembly that includes astopper and a securing ring. The stopper is inserted into the mouth ofthe vial and is configured to effectuate a circumferential seal. Thesecuring ring is engaged with the neck of the vial and at leastpartially overlies the stopper so as to retain the stopper within thevial mouth. The stopper is made of vulcanized rubber or similarresilient material that neither contaminates nor affects the containedmedicament. Vulcanized rubber has been determined to be a safe andeffective material for manufacturing vial caps for containing numeroustypes of medicaments. Vulcanized rubber, however, is infusible, andtherefore any needle holes in such caps are not heat-resealable.

[0005] The securing ring is typically configured such that a portion ofthe stopper is exposed and can be accessed by a needle, thereby allowingthe medicament to be withdrawn. Traditionally, securing rings arethreadably engaged with the vial or affixed therewith by a metalcrimping technique. In applications such as healthcare, a crimped metalsecuring ring is frequently preferred, since a crimped ring provides amechanism for assuring that the vial has not been opened or compromisedsubsequent to being filled or sterilized.

[0006] Referring to FIG. 1, a prior art cap for a medicament vial isdesignated generally by reference numeral 10. The cap 10 includes avulcanized rubber stopper 12, which is slidably received within the openend or mouth 8 of a cylindrical vial body 14. The vial body 14 is madeof glass or like material, and it defines a chamber 16 for receivingmedicament. An aluminum locking ring 18 surrounds the periphery of thestopper 12 and vial 14, and is crimped in place to secure, connect andseal the cap 10 to the vial body 14. The locking ring 18 includes acentral aperture which affords limited access to the stopper 12.

[0007] In order to fill such prior art vials with a sterile fluid orother substance, such as a medicament, it is typically necessary tosterilize the unassembled components of the vial, such as by autoclavingthe components and/or exposing the components to gamma radiation. Thesterilized components then must be filled and assembled in an asepticisolator of a sterile filling machine. In some cases, the sterilizedcomponents are contained within multiple sealed bags or other sterileenclosures for transportation to the sterile filling machine. In othercases, the sterilization equipment is located at the entry to thesterile filling machine. In a filling machine of this type, everycomponent is transferred sterile into the isolator, the storage chamberof the vial is filled with the fluid or other substance, the sterilizedstopper is assembled to the vial to plug the fill opening andhermetically seal the fluid or other substance in the vial, and then thecrimping ring is assembled to the vial to secure the stopper thereto.

[0008] One of the drawbacks associated with such prior art vials, andprocesses and equipment for filling such vials, is that the fillingprocess is time consuming, and the processes and equipment areexpensive. Further, the relatively complex nature of the fillingprocesses and equipment can lead to more defectively filled vials thanotherwise desired. For example, typically there are at least as manysources of failure as there are components. In many cases, there arecomplex assembly machines for assembling the vials or other containersthat are located within the aseptic area of the filling machine thatmust be maintained sterile. This type of machinery can be a significantsource of unwanted particles. Further, such isolators are required tomaintain sterile air within a barrier enclosure. In closed barriersystems, convection flow is inevitable and thus laminar flow, orsubstantially laminar flow, cannot be achieved. When operation of anisolator is stopped, a media fill test may have to be performed whichcan last for several, if not many days, and can lead to repeatedinterruptions and significant reductions in production output for thepharmaceutical or other product manufacturer that is using theequipment. In order to address such production issues,government-imposed regulations are becoming increasingly sophisticatedand are further increasing the cost of already-expensive isolators andlike filling equipment. On the other hand, governmental price controlsfor injectables and vaccines, including, for example, preventativemedicines, discourage such major financial investments. Accordingly,there is a concern that fewer companies will be able to afford suchincreasing levels of investment in sterile filling machines, thusfurther reducing competition in the injectable and vaccine marketplaces.

[0009] In order to address these and other concerns, the presentinventor has determined that it would be desirable to manufacture andfill vials by first assembling the stopper to the vial, sterilizing theassembled stopper and vial, such as by irradiation, and then filling theassembled vial by inserting a needle or like injection member throughthe stopper and introducing the medicament through the needle into thesterilized vial. One problem encountered with this approach, however, isthat when the needle or like injection member is inserted through thestopper and then withdrawn, it leaves a tiny hole in the stopper. Thematerial of the stopper is resilient in order to reduce the diameter ofthe hole, and therefore the hole is usually small enough to keep themedicament from leaking out. However, the hole typically is not smallenough to prevent air or other gases from passing through the hole andinto the vial, and therefore such holes can allow the medicament tobecome contaminated or spoiled.

[0010] It has been a practice in the pharmaceutical fields to addpreservatives to medicaments, such as vaccines, in order to preventspoilage of the medicaments upon exposure to air or other possiblecontaminants. Certain preservatives, however, have been determined tocause undesirable effects on patients. Consequently, many medicaments,including vaccines, are preservative free. These preservative-freemedicaments, and particularly preservative-free vaccines, are subject tocontamination and/or spoilage if contained within a vial wherein thestopper has a needle hole as described above.

[0011] As noted above, it is difficult to maintain the sterility ofstoppers and vials during the transportation, storage and assemblyprocess. There is a need, therefore, for vials and stoppers which can beassembled and then sterilized as a unit prior to filling the vialassembly with medicament. Although crimped metal rings provide amechanism for ensuring that the vial has not been compromised, the metalring does not allow the vial assembly to be easily sterilized as a unitby using a gamma sterilization technique or similar process. A metalring complicates the gamma sterilization process. Due to the density ofthe material, shadows (i.e., areas where the gamma radiation isprevented from passing through the material) are created which reducesthe assurance that the interior storage cavity has been completelysterilized. Also, the handling of the metal rings during the assemblyprocess can create dust and/or other particulates that can contaminatethe clean environment established for vial assembly and filling.

[0012] Additionally, the shape of conventional medicament vials can bedisadvantageous from a safety and/or handling perspective. For example,when a healthcare worker is withdrawing medicament from the vial,his/her fingers must grasp the cylindrical or spherical vial body. Inconventional vials, the vial body has an outer diameter that is greaterthan the outer diameter of the cap or closure. If the needle slips offof the cap due, for example, to the relative placement of the fingerswith respect to the cap, the healthcare worker's fingers are positionedin the slip path of the needle and therefore are likely to be pierced,causing a variety of safety concerns. In addition, such conventionalvials have a relatively high center of gravity making them prone totipping during handling, and further, define shapes and/orconfigurations that are not always well suited for needle filling and/orautomated handling in such needle filling and laser or other thermalresealing machines.

[0013] Accordingly, it is an object of the present invention to overcomeone or more of the above-described drawbacks and disadvantages of theprior art.

SUMMARY OF THE INVENTION

[0014] One aspect of the present invention is directed to a vialassembly for storing a substance, such as a medicament, comprising abody defining an opening, and a chamber in fluid communication with theopening for receiving therein the substance. The body defines a base, amid-portion, and an upper portion axially spaced from the base on anopposite side of the mid-portion relative to the base. Each of the baseand upper portion define a laterally-extending dimension that is greaterthan a maximum laterally-extending dimension of the mid-portion. In acurrently preferred embodiment of the present invention, each of thebase, mid-portion and upper portion are approximately circular in crosssection, and a maximum diameter of each of the base and upper portion isgreater than a maximum diameter of the mid-portion to thereby define anapproximate diabolo or spool shape. Preferably, the vial assemblyincludes a plastic tamper-resistant portion that is fixedly secured tothe body and extends at least partially over the stopper for preventingunnoticeable removal of the stopper.

[0015] In one embodiment of the present invention, the stopper includesa heat resealable portion overlying a substantially infusible portion.In another embodiment of the present invention, the stopper is athermoplastic stopper defining a needle penetration region that ispierceable with a needle to form a needle aperture therethrough, and isheat resealable to hermetically seal the needle aperture by applyinglaser radiation at a predetermined wavelength and power thereto. Thestopper comprises a thermoplastic body defining (i) a predetermined wallthickness in an axial direction thereof, (ii) a predetermined color andopacity that substantially absorbs the laser radiation at thepredetermined wavelength and substantially prevents the passage of theradiation through the predetermined wall thickness thereof, and (iii) apredetermined color and opacity that causes the laser radiation at thepredetermined wavelength and power to hermetically seal a needleaperture formed in the needle penetration region thereof in apredetermined time period of less than approximately 2 seconds andsubstantially without burning the needle penetration region.

[0016] Another aspect of the present invention is directed to a methodcomprising the following steps:

[0017] (i) providing a vial including a body defining an opening, achamber in fluid communication with the opening for receiving therein apredetermined substance, a base, a mid-portion, and an upper portionaxially spaced from the base on an opposite side of the mid-portionrelative to the base, wherein each of the base and upper portion definea laterally-extending dimension greater than a maximumlaterally-extending dimension of the mid-portion, and a heat-resealablestopper fusible in response to the application of thermal energythereto;

[0018] (ii) prior to filling the vial with substance, assembling thestopper and vial and forming a substantially gas-tight seal between thestopper and vial;

[0019] (iii) sterilizing the empty assembled stopper and vial;

[0020] (iv) supporting the vial with a vial support including a mountingsurface in engagement with the mid-portion of the vial, an upper surfacelocated on one side of the mounting surface, and a lower surface locatedon another side of the mounting surface;

[0021] (v) penetrating the stopper with a needle coupled in fluidcommunication with a source of predetermined substance;

[0022] (vi) introducing the predetermined substance through the needleand into the interior of the vial;

[0023] (vii) withdrawing the needle from the stopper; and

[0024] (viii) applying sufficient thermal energy to the penetratedregion of the stopper to fuse the penetrated region and form asubstantially gas-tight seal between the penetrated region and theinterior of the vial.

[0025] One advantage of the preferred embodiments of the presentinvention is that the vial defines a diabolo or spool-like shape, thusfacilitating the prevention of accidental needle sticks during use andotherwise facilitating handling of the vial during filling and otherprocessing. Another advantage of certain preferred embodiments of thepresent invention is that the stopper and vial may be assembled withouthuman intervention and prior to filling to thereby form hermeticallysealed, empty vials that may be sterilized and maintained in thesterilized condition prior to filling. Yet another advantage of certainpreferred embodiments of the present invention is that the plastic orlike tamper-resistant portion allows the empty vials to be sterilized,such as by the application of gamma, e-beam or other radiation thereto.

[0026] Other advantages of the present invention, and/or the disclosedembodiments thereof, will become more readily apparent in view of thefollowing detailed description of currently preferred embodiments andaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] So that those having ordinary skill in the art to which thepresent application appertains will more readily understand how to makeand use the same, reference may be had to the drawings wherein:

[0028]FIG. 1 is a cross-sectional view of a prior art cap for amedicament vial;

[0029]FIG. 2 is a cross-sectional view of a resealable stopper that maybe employed in vial assemblies embodying the present invention;

[0030]FIG. 3 is a cross-sectional view of the resealable stopper of FIG.2 shown with an injection needle or syringe inserted through the stopperfor introducing medicament into the vial, and a venting needle orsyringe inserted through the stopper for venting the vial during fillingof the medicament;

[0031]FIG. 4 is a cross-sectional view of another embodiment of theresealable stopper and vial;

[0032]FIG. 5 is a cross-sectional view of the crimpable locking memberof FIG. 4 for securing the resealable cap to the vial;

[0033]FIG. 6 is a cross-sectional view of the base portion of theresealable stopper of FIG. 4 made of a material compatible with thepredetermined medicament to be sealed within the vial, such asvulcanized rubber;

[0034]FIG. 7 is a cross-sectional view of the resealable portion of thestopper of FIG. 4 formed of a material that is fusible in response tothe application of thermal energy thereto in order to hermeticallyre-seal the stopper after inserting and removing a filling needle orlike instrument therethrough;

[0035]FIG. 8 is an enlarged, partial, cross-sectional view of theresealable portion of FIG. 7 and showing the penetrable portion thereoffor receiving a needle or like instrument therethrough;

[0036]FIGS. 9A through 9C are somewhat schematic, cross-sectional,sequential views illustrating an exemplary apparatus and method forsterilizing the resealable stoppers of the vials of the presentinvention by direct heat cauterization prior to introducing the fillingneedle or like instrument therethrough;

[0037]FIG. 10 is a somewhat schematic, partial, cross-sectional view ofan apparatus for sterilizing the resealable stoppers of the vials of thepresent invention by laser cauterization prior to introducing thefilling needle or like instrument therethrough;

[0038]FIG. 11 is a somewhat schematic, partial, cross-sectional view ofan apparatus for needle filling the vial assemblies of the presentinvention with a predetermined medicament or other substance to becontained therein;

[0039]FIGS. 12a through 12 d are somewhat schematic, cross-sectional,sequential views illustrating an apparatus and method for hermeticallysealing the penetrated region of the resealable stoppers of the vials ofthe present invention by direct heat sealing after withdrawing thefilling needle therefrom;

[0040]FIGS. 13A through 13C are somewhat schematic, cross-sectional,sequential views illustrating an apparatus and method for hermeticallysealing the penetrated region of the resealable stoppers of the vials ofthe present invention by laser sealing after withdrawing the fillingneedle therefrom;

[0041]FIG. 14A is a side elevational view of a vial embodying thepresent invention;

[0042]FIG. 14B is a cross-sectional view of the vial of FIG. 14A takenalong line 14B-14B and illustrating a three-piece closure assemblypartially inserted into the mouth of the vial, wherein the closureassembly includes a stopper, a heat-resealable portion and anover-molded securing or locking ring;

[0043]FIG. 14C is a cross-sectional view of the over-molded vial of FIG.14 taken along line 14C-14C thereof, wherein the vial has a relativelyenlarged base portion;

[0044]FIG. 15 is a cross-sectional view of another vial embodying thepresent invention, and including a closure or cap wherein theover-molded securing ring is formed in an annular recess defined betweenthe outer periphery of the stopper and the vial body;

[0045]FIGS. 16A and 16B illustrate representative sequential views of anexemplary over-molding process for making over-molded vials embodyingthe present invention;

[0046]FIGS. 17A through 17C are cross-sectional, sequential views of analternate over-molding process for making over-molded vials embodyingthe present invention, wherein both the vial closure and the baseportion of the vial are formed by injection molding;

[0047]FIG. 18 is a cross-sectional view of another vial embodying thepresent invention wherein the base and locking ring are snap fit to thevial body, and the tamper-resistant cover is snap fit to the lockingring;

[0048]FIG. 19 is a cross-sectional view of another vial embodying thepresent invention wherein the stopper and securing ring are formed usinga sequential molding process;

[0049]FIG. 20 is a cross-sectional view of the stopper of the vial ofFIG. 19;

[0050]FIG. 21 is a cross-sectional view of the stopper and securing ringof the vial of FIG. 19;

[0051]FIG. 22A is a perspective view of the vial of FIG. 18 with thetamper-resistant cover removed;

[0052]FIG. 22B is a perspective view of the vial of FIG. 18 includingthe tamper-resistant cover fixedly secured thereto;

[0053]FIG. 22C is a perspective view of the vial of FIG. 18 illustratingthe frangible portion of the tamper-resistant cover flipped upwardly toexpose the resealable stopper and allow same to be penetrated with theneedle of a syringe to withdraw the medicament of other substancecontained within the vial into the syringe;

[0054]FIG. 23 is a side elevational view of another vial embodying thepresent invention wherein the locking ring, cover and base are connectedtogether by ultrasonic welding;

[0055]FIG. 24 is a cross-sectional view of the vial of FIG. 23;

[0056]FIG. 25 is a partially exploded, perspective view of the vial ofFIG. 23;

[0057]FIG. 26 is a perspective view of the vial assembly of FIG. 23 withthe tamper-resistant cover removed;

[0058]FIG. 27 is an exploded, perspective view of the vial of FIG. 23;

[0059]FIG. 28 is partially cut-away, perspective view of the vial ofFIG. 23;

[0060]FIG. 29 is a cross-sectional view of another vial embodying thepresent invention;

[0061]FIG. 30 is a perspective, exploded view of the vial of FIG. 30;

[0062]FIG. 31 is a perspective, partial, cut-away view of the vial ofFIG. 30;

[0063]FIG. 32 is a perspective, partly exploded view of a needlemanifold used in a needle filling module of a sterile filling machinefor needle filling the vials with a medicament or other substance to becontained therein;

[0064]FIG. 33 is a front perspective view of the needle manifold of FIG.32 located in an “up” position within a sterile enclosure of a sterilefilling machine, and with a plurality of vials mounted within atransport system including a star wheel and associated guide, that arealigned with the needles and ready for needle filling;

[0065]FIG. 34 is a front perspective view of the needle manifold andtransport system of FIG. 33 showing the needle manifold in a “down”position with the needles penetrating the resealable stoppers of thevials and filling the interiors of the vials with a medicament or othersubstance to be contained therein;

[0066]FIG. 35 is a rear perspective view of the needle manifold andtransport system of FIG. 33 showing the needle in the “down” or fillposition;

[0067]FIG. 36 is a perspective view of a laser sealing and infraredsense manifold mounted downstream of the needle manifold of FIGS. 32-35in a sterile enclosure of a sterile filling machine for laser resealingthe needle holes in the filled vials;

[0068]FIG. 37 is a partly exploded, end elevational view of a moduleincluding a needle manifold, laser optic assemblies, and sensors, forneedle filling and laser resealing the vials therein, and with someparts removed for clarity;

[0069]FIG. 38 is an end elevational view of the module of FIG. 37showing the needle manifold clamped to the drive plate, and with someparts removed for clarity;

[0070]FIG. 39A is an end elevational view of the module of FIG. 37, withparts removed for clarity, without any vials received within the module,and showing the needles in the “up” position;

[0071]FIG. 39B is an end elevational view of the module of FIG. 39Ashowing vials received within the module and ready to be needle piercedand filled;

[0072]FIG. 39C is an end elevational view of the module of FIG. 39Ashowing the needle manifold in the “down” position with the needlespiercing the resealable stoppers for allowing the medicament or othersubstance to be pumped through the needles to fill the vials;

[0073]FIG. 40A is an end elevational view of the module with partsremoved for clarity, and showing an exemplary laser optic assembly andsensor;

[0074]FIG. 40B is an end elevational view of the module of FIG. 40Ashowing the needle piercing the resealable stopper to, in turn, fill theinterior chamber of the respective vial with a medicament or othersubstance to be contained therein;

[0075]FIG. 40C is an end elevational view of the module of FIG. 40Ashowing the needle removed from the resealable stopper, the laser beambeing transmitted onto the penetration point of the needle, and the IRsensor sensing the temperature of the resealed portion of the stopper toensure the integrity of the seal;

[0076]FIG. 41 is a partly exploded view of the needle manifold of themodule with some parts removed for clarity;

[0077]FIG. 42 is a perspective view of the module showing an e-beam unitmounted within the module for sterilizing selected surfaces of the vialand needles located within the module chamber, and with the needlemanifold and other parts removed for clarity;

[0078]FIG. 43 is a top plan, somewhat schematic view of the modulemounted adjacent to a screw-type conveyor for driving the vials throughthe module;

[0079]FIG. 44 is a top plan, somewhat schematic view of the modulemounted adjacent to a closed-loop conveyor, an inlet conveyor fortransferring the empty vials onto the closed loop conveyor, and anoutlet conveyor for receiving the filled and resealed vials;

[0080]FIG. 45 is a cross-sectional view of another vial embodying thepresent invention wherein the filling needle may penetrate the stopperin a marginal portion of the penetrable region of the stopper at anacute angle relative to the axis of the vial, and the resealed portionof the stopper may be concealed under the tamper-resistant cover uponremoving the frangible portion thereof;

[0081]FIG. 46 is an upper perspective view of the vial of FIG. 45 withthe tamper-resistant cover removed;

[0082]FIG. 47 is another cross-sectional view of the vial of FIG. 45including the tamper-resistant cover secured thereto, and illustratingthe manner in which the laser resealed portion of the stopper isvisually concealed under the tamper-resistant cover upon removal of thefrangible portion thereof; and

[0083]FIG. 48 is an upper perspective view of the vial of FIG. 47.

DETAILED DESCRIPTION OF THE CURRENTLY PREFERRED EMBODIMENTS

[0084] Reference is now made to the accompanying figures for the purposeof describing, in detail, preferred embodiments of the presentdisclosure. The figures and accompanying detailed description areprovided as examples of the disclosed subject matter and are notintended to limit the scope thereof.

[0085] Turning to FIG. 2, a heat-resealable cap or stopper that may beused in the vials of the present invention is indicated generally by thereference numeral 110. The cap 110 includes a resilient base 112 made ofvulcanized rubber or like material which is known to those of ordinaryskill in the pertinent art, and acceptable for use in the manufacture ofend caps or the portions thereof placed in contact with, or otherwiseexposed to medicaments or other substances to be contained in the vials,such as vaccines. The base 112 defines a lower peripheral wall 115shaped and dimensioned to be slidably received within the open end of avial 114. The vial 114 may be made of any of numerous different types ofglass or plastic, or any other material that is currently or laterbecomes known for use in connection with making vials, such as vials forstoring medicaments or other substances. The vial 114 defines therein achamber 116 for receiving medicament. As described further below, thevial preferably defines a “diabolo” or spool-like shape to, for example,facilitate handling of the vial during sterilization, filling and/orother processing of the vial, and during use of the vial. The base 112of the cap 110 further defines an upper peripheral wall 117 also shapedand dimensioned to be slidably received within the open end of the vial114, and a peripheral sealing flange 118 projecting outwardly from theupper end of the peripheral wall 117. The vial 114 defines at its openend a peripheral flange 120. As shown in FIGS. 2 and 3, the peripheralflange 118 of the base 112 sealingly engages the peripheral flange 120of the vial 114 to seal the interface between the cap and vial. The base112 further defines an upper recess 122 formed within the upperperipheral wall 117, and an annular rim 124 projecting inwardly from theupper end of the peripheral wall.

[0086] A resealable portion 126 is fixedly received within the upperrecess 122 of the base 112 to form the assembled cap 110. The resealableportion 126 defines an upper peripheral flange 128, an annular recessedportion or recess 130, and a base 132 located on the opposite side ofthe annular recess 130 relative to the flange, and projecting outwardlyfrom the recess. As can be seen in FIGS. 2 and 3, the annular recess 130and base 132 of the resealable portion 126 are dimensioned and shapedcomplementary to (or define the mirror image of) the interior surfacesof the upper recess 122 and annular rim 124 of the base 112.Accordingly, the resealable portion 126 is pressed, snapped or otherwisereceived within the upper recess 122 such that the annular rim 124 isreceived within the annular recess 130 to thereby fixedly secure theresealable portion within the base.

[0087] The resealable portion 126 is preferably made of a resilientpolymeric material, such as a blend of a first polymeric material soldunder the registered trademark KRATON® or DYNAFLEX® and a secondmaterial in the form of a low-density polyethylene, such as thepolyethylene sold by Dow Chemical Co. under the trademarks ENGAGE™ orEXACT™. In some embodiments, the first and second materials are blendedwithin a range of about 50:50 by weight to about 90:10 by weight (i.e.,first material : second material). In one embodiment, the blend of thefirst and second materials is about 50:50 by weight. The benefits of thepreferred blend over the first material by itself are improved water orvapor barrier properties, and thus improved product shelf life; improvedheat sealability; a reduced coefficient of friction; improvedmoldability or mold flow rates; and a reduction in hysteresis losses. Asmay be recognized by those skilled in the pertinent art, these numbersand materials are only exemplary, however, and may be changed if desiredor otherwise required.

[0088] An important feature of the resealable portion 126 is that it beresealable to form a gas-tight seal after inserting a needle, syringe orlike injection member through the resealable member. Preferably, theresealable portion can be sealed by heating the area punctured by theneedle as described further below. One advantage of the blended polymerdescribed above is that it is known to minimize the degree to which themedicament can be absorbed into the polymer in comparison to eitherKRATON® or DYNAFLEX® itself.

[0089] An aluminum locking or crimping ring 134 defining an upperperipheral flange 136 and a lower peripheral flange 138 may be mountedover the end cap 110 and vial 114. The upper and lower flanges 136 and138, respectively, of the locking ring are crimped or otherwise pressedagainst the adjacent surfaces of the cap and vial to press the sealingflanges of the cap against the vial and thereby maintain a fluid-tightand/or gas-tight seal between the cap and vial. Alternatively, thelocking ring may be formed of a non-metallic material, such as a plasticmaterial, that may be snap-fit to the underside of the peripheral flange120, or otherwise secured to the flange of the vial body, as describedfurther below.

[0090] As shown in FIG. 3, the heat-resealable cap 110 is shown with ahypodermic or other type of needle 140 inserted through the resealableportion 126 and the resilient base 112 in order to dispense medicamentinto the chamber 116 of the vial. A venting needle 142 likewise may beinserted through the resealable portion 126 and the resilient base 112in order to allow gas to escape from the vial 114 as the medicament isdeposited into the vial. Alternatively, the needle 140 may define one ormore axially-elongated grooves in an outer surface thereof to allow gaswithin the vial to vent therethrough and thereby eliminate the need forthe venting needle 142, or the needle may take the form of a “double” or“multi” lumen needle wherein the one lumen of the needle delivers themedicament or other substance to be contained within the vial, andanother lumen permits the gas displaced by the medicament or othersubstance to flow out of the vial. The apparatus and method fordispensing medicament or other substances into the vial may take a formas shown in U.S. Pat. No. 5,641,004 to Daniel Py, issued Jun. 24, 1997,and more preferably, may take a form as shown in U.S. Provisional PatentApplication No. 60/484,204, filed Jun. 30, 2003, entitled “MedicamentVial Having A Heat-Sealable Cap, And Apparatus And Method For FillingThe Vial”, each of which is hereby expressly incorporated by referenceas part of the present disclosure.

[0091] In operation, the resealable portion 126 is inserted into thebase 112, and the assembled end cap 110 is slidably inserted into theopen end of the vial 114. The locking ring 134 is then crimped in placeto lock the cap 110 to the vial and maintain the gas-tight seal at theinterface of the cap and vial. The assembled cap 110 and vial 114preferably are then sterilized, such as by exposing the assembly toirradiation, such as laser, beta, gamma or e-beam radiation, in a mannerknown to those of ordinary skill in the pertinent art. Themedicament-dispensing needle 140 is then inserted through the resealableportion 126 and the resilient base 112 until the free end of the needleis received into the chamber 116 of the vial to, in turn, dispensemedicament into the chamber. The venting needle 142 is likewise insertedthrough the resealable portion 126 and the resilient base 112 in orderto draw gas from the sealed vial as the liquid medicament is depositedwithin the chamber of the vial. Once the medicament has been depositedwithin the chamber of the vial, the needles 140 and 142 are withdrawnfrom the cap 110, and as described further below, a heat or other energysource is applied to the portions of the resealable portion 126punctured by the needles 140 and 142 to, in turn, seal the puncturedareas and hermetically seal the medicament within the vial.

[0092] One advantage of the illustrated vial assemblies is that thestopper may be resealed following the deposit of medicament into theinterior of the vials, thereby rendering the vials particularly suitablefor use with preservative-free medicaments, such as preservative-freevaccines. Accordingly, a further advantage of the illustrated vialassemblies is that the medicament need not contain a preservative, andtherefore the above-described drawbacks and disadvantages of suchpreservatives can be avoided.

[0093] Another advantage of the illustrated vial assemblies is that themedicament within the resealed chambers of the vials is not contaminatedor otherwise affected by impurities or other agents in the atmospherewhere the vial is stored or transported.

[0094] In FIGS. 4 through 8 another resealable stopper or cap that maybe employed in the vials of the present invention is indicated generallyby the reference numeral 210. The resealable stopper 210 is essentiallythe same as the stopper 110 described above, and therefore likereference numerals preceded by the numeral “2” instead of the numeral“1” are used to indicate like elements. As shown best in FIGS. 4 and 6,the base 212 of the cap defines on the interior side of its upperperipheral wall 217 an annular groove 230. As shown best in FIGS. 4 and7, the resealable portion 226 defines on the peripheral surface of itsbase 232 an annular raised portion or protuberance 224 dimensioned to befrictionally received within the corresponding annular groove 230 of thebase 212 to thereby secure the resealable portion to the base. As shownin FIG. 6, the base 212 further defines on the exterior side of itslower peripheral wall 215 a plurality of raised annular portions orprotuberances 244 axially spaced relative to each other for frictionallyengaging the interior wall of the vial 214 to thereby secure the capwithin the vial and facilitate maintaining a hermetic seal between thecap and vial. As shown best in FIGS. 7 and 8, the resealable portion 226defines on its top surface an annular raised portion or protuberance 246defining a circular surface portion 248 therein for receiving a fillingneedle or like instrument, as described further below. As shown in FIG.5, the locking or crimping ring 234 defines a central aperture 250 inits upper side for receiving therethrough the annular raised portion 246of the resealable portion 226.

[0095] Preferably, the resealable cap 210 and vial 214 are assembled andthe locking ring 234 is crimped or otherwise secured in place asdescribed above and shown in FIG. 4 prior to introducing any medicamentor other fluid into the vial. Then, one or more of the empty cap/vialassemblies are enclosed, sterilized, and may be transported inaccordance with the teachings of the present inventor's commonly ownedU.S. Pat. No. 5,186,772, entitled “Method Of Transferring Articles,Transfer Pocket And Enclosure”, and/or U.S. patent application Ser. No.10/241,249, entitled “Transfer Port And Method For Transferring SterileItems”, filed Sep. 10, 2002, each of which is hereby expresslyincorporated by reference as part of the present disclosure. The emptycap/vial assemblies may be placed in an internal bag or “pocket” whichis closed and, if desired, provided with a sterilization indicator.Then, the internal pocket may be placed within a transfer pocketincluding a sealing frame defining an annular groove on a peripheral'surface thereof. The transfer pocket is stretched over the surface ofthe frame and closed by an elastic band overlying the transfer pocketand received within the peripheral groove. The transfer pocket likewisemay include therein a sterilization indicator. Preferably, the assembledtransfer and internal pockets are sealed within an “external” pocket andthe assembled pockets are subject to sterilization, such as by exposureto gamma radiation, to sterilize the pockets and the empty cap/vialassemblies within the pockets. The transfer pockets then can be used tostore and/or transport the sterilized assemblies to a filling systemwithout contaminating the sterilized assemblies. As further described inthe above-mentioned patent and patent application, the filling system islocated within a sterile enclosure, and the empty vials are introducedinto the enclosure by removing and discarding the external pocket, andconnecting the sealing frame of the transfer pocket to a window ortransfer port of the enclosure. As further disclosed in theabove-mentioned patent and patent application, an adhesive material ispreferably superimposed on the sealing frame for securing the transferpocket to the transfer port of the filling system enclosure. Prior toreleasing the vial assemblies into the filling system enclosure, thesterilization indicators may be checked in order to ensure that thesterile condition of the vial assemblies were maintained throughoutstorage and transfer. As described in the above-mentioned patent andpatent application, the portion of the transfer pocket overlying theframe is then cut away and simultaneously sterilized along the trimmedsurfaces to destroy any microorganisms or germs thereon, and to allowthe internal pocket to be received through the transfer port and intothe enclosure.

[0096] Once received within the enclosure, the internal pocket is openedand the empty vial assemblies are removed and loaded into a fillingmachine located within the sterile enclosure. Once loaded into thefilling machine, the resealable portion of each empty vial assembly maybe sterilized again in order to further ensure that no contaminatesenter the vial during the filling process. The resealable portions ofthe stoppers may be sterilized at this stage by direct heatcauterization, laser cauterization, or the application of another formof radiation, such as e-beam radiation.

[0097] As shown in FIGS. 9A through 9C, an apparatus for cauterizing theresealable stoppers or caps by application of heat thereto is indicatedgenerally by the reference numeral 252. The apparatus 252 comprises ahousing 254 mounted over a vial support 256. The vial support 256 may beadapted to hold a single vial, or preferably, is adapted hold aplurality of vials. The embodiment of the support adapted to hold aplurality of vials defines a channel 258 for receiving therein thevials, and a pair of opposing shoulders 260 formed at the upper edge ofthe channel for supporting thereon the flange 220 of the vial. Ifdesired, a vibratory drive (not shown) may be drivingly connected to thesupport 256 to vibrate the support and, in turn, move the vials throughthe channel at a predetermined rate. Alternatively, the vial support 256may be mounted on, or otherwise take the form of a conveyor for movingthe vials through the sterile filling machine. As may be recognized bythose skilled in the pertinent art based on the teachings herein,however, any of numerous different drive systems that are currently, orlater become known, may be equally employed to move the vials throughthe filling machine.

[0098] The housing 254 defines a peripheral sealing surface 262 formedon the free end of the housing for sealingly engaging the upper flangesurface 236 of each locking member 234. As shown best in FIG. 9b, theperipheral sealing surface surrounds the aperture 250 formed through thelocking member and exposing the penetrable region 248 of the resealableportion 226 of the stopper. Preferably, the peripheral sealing surface262 forms a substantially fluid-tight seal between the housing and thestopper. A heating surface 264 projects outwardly from the free end of acentral support 266 of the housing for contacting the penetrable surface248 of the resealable portion and cauterizing the surface. An annularconduit 268 extends about the periphery of the heating surface 264 andis coupled in fluid communication to a vacuum source 270 for drawing airthrough the conduit and away from the cauterized surface 248, asindicated by the arrows in the Figures. The housing 254 is drivinglyconnected to a drive source 272 for moving the housing and thus theheating surface 264 into and out of engagement with the exposedpenetrable surface portion 248 for cauterizing the surface, as indicatedby the arrows in the Figures. As may be recognized by those skilled inthe pertinent art based on the teachings herein, the drive source 272may take the form of any of numerous different types of drive sourcesthat are currently, or later become known, for performing the functionof the drive source as described herein, such as a pneumatic drive, or asolenoid-actuated or other type of electric drive. Similarly, theheating surface 264 may take any of numerous different shapes andconfigurations, and may be heated in any of numerous different ways thatare currently or later become known, such as by an electric resistanceheater (or “hot wire”). Preferably, however, the heating surface 264defines a surface shape and contour corresponding to the desired shapeand contour of the penetrable surface region 248 of the cap.

[0099] In the operation of the apparatus 252, and as shown typically inFIG. 9A, each vial is first introduced into the cauterizing station withthe penetrable surface region 248 of the resealable portion 226 alignedwith the heating surface 264. Then, the drive source 272 is actuated todrive the housing 254 downwardly until the peripheral sealing surfaces262 sealingly engage the upper flange surface 236 of the respectivelocking member 234, and the heating surface 264 simultaneously engagesthe exposed penetrable surface portion 248 of the resealable portion226. The heated surface 264 is maintained at a predeterminedtemperature, and is held in contact with the exposed surface portion 248for a predetermined time period, sufficient to cauterize the exposedsurface portion. One advantage of the construction of the resealableportion 226 as shown in FIGS. 7 and 8, is that the cauterization processdeforms the annular protuberance 246 into a contour conforming to thatof the heated surface, thus allowing an operator (or optical or otherautomatic sensing system) to visually determine whether each cap hasbeen properly cauterized prior to filling. As shown in FIG. 9c, aftercauterizing the exposed surface, the drive source 272 is actuated todrive the housing 254 upwardly and out of engagement with the cap,another vial is moved under the housing, and the process is repeateduntil all desired vials are cauterized. As described further below, uponexiting the cauterizing station of FIGS. 9A through 9 c, the vials arepreferably then moved into a filling station to promptly fill thesterilized vials. The cauterization and filling stations are preferablymounted within a sterile enclosure with a laminar gas flow through theenclosure to facilitate maintaining the sterile conditions, asdescribed, for example, in the above-mentioned patent and patentapplication.

[0100] In the embodiment illustrated in FIGS. 9A through 9C, thetemperature of the heating surface is within the range of approximately250° C. to 300° C., and the cycle times (i.e., the time period duringwhich the heating surface is maintained in contact with the exposedsurface 248 of the resealable portion) are within the range ofapproximately 1.0 to 3.0 seconds. The present inventor has determinedthat these temperatures and cycle times may achieve at leastapproximately a 6 log reduction in bio-burden testing to therebyeffectively sterilize the surface.

[0101] In FIG. 10, an alternative apparatus for cauterizing theresealable caps is indicated generally by the reference numeral 274. Theapparatus 274 differs from the apparatus 252 of FIGS. 9A through 9C inthat the thermal energy required for sterilizing the filling area of theresealable portion is supplied by a laser (referred to herein as “lasercauterization”). The laser cauterization apparatus 274 comprises a laseror other suitable radiation source 276 optically coupled to a scanningmirror 278 mounted over the vial/cap assembly. Although not shown inFIG. 10, the vials are preferably mounted within the same type ofsupport as shown in FIGS. 9A through 9C in order to allow the resealablecaps to be rapidly cauterized in succession prior to filling each vialwith medicament, as described further below.

[0102] In one embodiment, the laser 276 is a commercially available CO₂or YAG laser. The CO₂ laser operates at a wavelength of approximately10.6 μm. At this wavelength, absorption of the laser energy is governedin part by the electrical conductivity of the material. Therefore, aninsulating material, such as the elastomeric material of the resealableportion 226, absorbs and converts most of the incident energy intothermal energy to cauterize the receiving surface 248. The YAG laseroperates at wavelength of approximately 1.06 μm. At this frequency,absorption is governed in part by the lattice atoms. Thus, a clear ortransparent polymer with little ionization would be permeable to thelaser beam. Accordingly, when employing a YAG laser (as with other lasersources, as described below), it is desirable to add a colorant to theelastomeric material of the resealable portion in order to enhance itsabsorption of the laser energy. With the YAG laser, the superficiallayer of the penetrable region of the resealable portion, and any germs,bacteria or other contaminants thereon, are transformed into plasma torapidly and thoroughly sterilize the effected surface. If necessary, aUV-filtration coating may be applied to the surfaces of the sterilefilling enclosure to prevent the operators from receiving anyunnecessary UV exposure.

[0103] The present inventor has demonstrated that beam energies in therange of approximately 15 to 30 W are sufficient to effectivelycauterize the surface 248 of the elastomeric resealable portion. Inaddition, bio-burden testing has demonstrated that laser energies ofapproximately 20 W or greater may achieve about a 6.0 log reduction. Atthese energies, the apparatus may effectively sterilize the surface 248within a cycle time of approximately 0.5 seconds. Accordingly, asignificant advantage of the laser cauterization apparatus and method isthat they may involve significantly shorter cycle times than variousdirect heat methods. Yet another advantage of laser cauterization, isthat it involves both a non-contact method and apparatus, and thereforethere is no need to be concerned with the cleaning of a contact head orlike heating surface.

[0104] Turning to FIG. 11, after direct heat or laser cauterization ofthe resealable portion 226 of each vial, the vial is moved within thesupport 256 (such as by vibratory drive) into a filling station 280. Thefilling station 280 includes a needle or like injection member 282reciprocally mounted over the support 256, as indicated by the arrows inFIG. 11, and axially aligned with the penetrable region 248 of theresealable portion 226 of each vial assembly passing therethrough. Adrive source 284 is drivingly connected to the needle 280 forreciprocally driving the needle 282 into and out of engagement with eachcap or stopper 210. A medicament or other formulation reservoir 286 iscoupled in fluid communication with the needle 282 for introducing apredetermined medicament or other formulation through the needle andinto the vial. In the illustrated embodiment, the needle 282 defines aplurality of fluid conduits therein, including a first fluid conduit 288for injecting the predetermined medicament or other formulation into thevial, as indicated by the arrow in FIG. 11, and a second fluid conduit290 coupled in fluid communication with a vacuum source 292 forwithdrawing air or other gases from the interior cavity 216 of the vialprior to and/or during the filling of the cavity with the medicament orother formulation. In the illustrated embodiment, the needle 282 is a“double lumen” needle, defining a central fluid conduit 288 forinjecting the predetermined medicament or other formulation into thevial, and an outer annular fluid conduit 290 for drawing the displacedair or other gases out of the interior cavity of the vial.Alternatively, the outer fluid conduit 290 of the double-lumen needlemay be defined by one or more axially-elongated grooves formed in theouter wall of the needle that form fluid-flow passageways between theneedle and the pierced portion of the resealable stopper. As may berecognized by those of ordinary skill in the pertinent art based on theteachings herein, the needles used to needle fill the vial assemblies ofthe present invention may take any of numerous different shapes and/orconfigurations that are currently known, or later become known forperforming the functions of the needles as described herein.

[0105] As shown in FIGS. 12a through 12 d, after filling the vial withthe medicament or other formulation and withdrawing the needle 282 fromthe cap or stopper 210, the penetrated region of the cap defines aneedle hole 294 along the path of the withdrawn needle (FIG. 12b). Uponwithdrawing the needle, the vulcanized rubber base 212 of the stopper issufficiently resilient to close upon itself in the penetrated region andthereby maintain the vial in a sealed condition. However, as describedabove, vapors, gases and/or liquid may be allowed over time to passthrough the needle hole of the vulcanized rubber base, and thereforeeach vial/cap assembly is passed through a sealing station, as showntypically in FIG. 12c, to heat seal the resealable portion 226 of thecap promptly after withdrawing the needle therefrom. As shown typicallyin FIG. 12c, a heated member or surface 264 may be reciprocally mountedover, and axially aligned with the penetrable region 248 of the vial/capassembly received within the filling station. A drive source 272 isdrivingly connected to the heated member 264 to reciprocally drive theheated member into and out of engagement with the resealable portion ofeach cap. As shown typically in FIG. 12c, the heated member 264 ismaintained at a sufficient temperature, and maintained in engagementwith the penetrated region of the resealable portion 226 to fuse theelastomeric material and hermetically seal the needle hole 294. As aresult, and as shown typically in FIG. 12d, the needle hole iseliminated from the exterior region of the resealable portion to therebymaintain a hermetic e seal between the cap and vial.

[0106] As may be recognized by those skilled in the pertinent art basedon the teachings herein, the drive source and heating member/surface ofFIGS. 12a through 12 d may take the form of any of numerous differentdrive sources and heating members as described above. As indicatedtypically in FIG. 12c, however, the heating member 264 may define asmaller width than the heating member/surface described above forcauterizing the penetrable region of the cap prior to filling. Inaddition, the temperature of the heating member 264 for sealing may behigher than that of the heating member described above in order torapidly melt and seal the penetrated region. One advantage of resealablestoppers is that the base thermally insulates the heated region from themedicament in the vial to thereby maintain the medicament in the vialwithin an appropriate temperature range throughout the cauterization andheat sealing processes and thereby avoid any thermal damage to themedicament.

[0107] Alternatively, and as shown in FIGS. 13A through 13C, the lasersource 276 and scanning mirror 278 may be employed to heat seal thepenetrated region 294/248 of the resealable portion. Accordingly, thesame type of laser source 276 and scanning mirror 278 as described abovemay be employed in the heat sealing station to perform this function, oralternatively, a different type of laser system may be employed. In oneembodiment, a CO₂ laser of approximately 50 W is employed to seal aregion approximately 0.10 inch in diameter in the resealable stopper.

[0108] In the currently-preferred embodiments of the present invention,each sealable cap or stopper is formed of a thermoplastic materialdefining a needle penetration region that is pierceable with a needle toform a needle aperture therethrough, and is heat resealable tohermetically seal the needle aperture by applying laser radiation at apredetermined wavelength and power thereto. As described further below,each cap or stopper includes a thermoplastic body or body portiondefining (i) a predetermined wall thickness in an axial directionthereof, (ii) a predetermined color and opacity that substantiallyabsorbs the laser radiation at the predetermined wavelength andsubstantially prevents the passage of the radiation through thepredetermined wall thickness thereof, and (iii) a predetermined colorand opacity that causes the laser radiation at the predeterminedwavelength and power to hermetically seal the needle aperture formed inthe needle penetration region thereof in a predetermined time period andsubstantially without burning the needle penetration region and/or thecover portion of the stopper (i.e., without creating an irreversiblechange in molecular structure or chemical properties of the material).In some embodiments, the predetermined time period is approximately 2seconds, and is preferably less than or equal to about 1.5 seconds. Insome of these embodiments, the predetermined wavelength of the laserradiation is about 980 mn, and the predetermined power of each laser ispreferably less than about 30 Watts, and preferably less than or equalto about 10 Watts, or within the range of about 8 to about 10 Watts.Also in some of these embodiments, the predetermined color of thematerial is gray, and the predetermined opacity is defined by a darkgray colorant added to the stopper material in an amount within therange of about 0.3% to about 0.6% by weight.

[0109] In addition to the thermoplastic materials described above, thethermoplastic material may be a blend of a first material that ispreferably a styrene block copolymer, such as the materials sold undereither the trademarks KRATON or DYNAFLEX, such as DYNAFLEXG2706-10000-00, and a second material that is preferably an olefin, suchas the materials sold under either the trademarks ENGAGE or EXACT, suchas EXACT 8203. In some embodiments of the invention, the first andsecond materials are blended within the range of about 50:50 by weightto preferably about 90:10 by weight, and most preferably about 90:5 byweight (i.e., first material:second material). The benefits of thepreferred blend over the first material by itself are improved water orvapor barrier properties, and thus improved product shelf life; improvedheat sealability; a reduced coefficient of friction; improvedmoldability or;mold flow rates; and a reduction in hysteresis losses.

[0110] Alternatively, the thermoplastic material of the resealablestoppers may take the form of a styrene block copolymer sold by GLSCorporation of McHenry, Ill. under the designation LC 254-071. This typeof styrene block copolymer compound exhibits approximately the followingphysical properties: (i) Shore A Hardness: about 28-29; (ii) SpecificGravity: about 0.89 g/cm³; (iii) Color: approximately grey to dark grey;(iv) 300% Modulus, flow direction: about 181-211 psi; (v) TensileStrength at Break, flow direction: about 429-498 psi; (vi) Elongation atBreak, flow direction: about 675%-708%; and (vii) Tear Strength, flowdirection: about 78-81 lbf/in. In one embodiment, the predeterminedcolor and opacity of the thermoplastic is defined by a grey colorantthat is provided in an approximately 3% color concentrate (i.e., thereis an approximately 33:1 ratio of the concentrate to the natural resinor TPE). The color concentrate contains about 88.83% carrier or baseresin, and the remainder is pigment. In one embodiment, the pigment isgrey carbon black. Thus, the pigment is about 0.34% by weight of theresulting thermoplastic.

[0111] In addition, if desired, a lubricant of a type known to those ofordinary skill in the pertinent may be added to the thermoplasticcompound, such as the aforementioned styrene block copolymer compound,in order to prevent or otherwise reduce the formation of particles uponpenetrating the needle penetration region of the thermoplastic portionwith a needle or other filling member. In one embodiment, the lubricantis a mineral oil that is added to the styrene block copolymer or otherthermoplastic compound in an amount sufficient to prevent, orsubstantially prevent, the formation of particles upon penetrating samewith the needle or other filling member. In another embodiment, thelubricant is a silicone, such as the liquid silicone sold by Dow ComingCorporation under the designation “360 Medical Fluid, 350 CST”, that isadded to the styrene block copolymer or other thermoplastic compound inan amount sufficient to prevent, or substantially prevent, the formationof particles upon penetrating same with the needle or other fillingmember.

[0112] Each of the vials of the present invention may be made of any ofnumerous different materials that are currently, or later become knownfor making vials. For example, in some embodiments of the presentinvention, the vials are made of glass. In one such example, the vialbody is made of glass; however, a laterally extending base is made ofplastic, and is secured to the base of the glass vial body by anadhesive, snap-fit, over-molding, or other known joining mechanism, andthe locking ring likewise is made of plastic and is secured to the openend of the vial body by an adhesive, snap-fit, over-molding, or otherknown joining mechanism. In other currently-preferred embodiments of thepresent invention, the vial bodies are made of a thermoplastic material,such as the thermoplastic material sold under the trademark TOPAS byTicona Corp. of Summit, N.J. In some embodiments of the presentinvention, the TOPAS™ material is sold under any of the followingproduct codes: 5013, 5513, 6013, 6015, and 8007, and is a cyclic olefincopolymer and/or cyclic polyolefin.

[0113] As may be recognized by those skilled in the pertinent art basedon the teachings herein, the specific formulations of the polymericcompounds used to form the stoppers and the vials or other containers ofthe present invention can be changed as desired to achieve the desiredphysical characteristics, including sorption (both absorption andadsorption), and moisture-vapor transmission (“MVT”). For example, thewall thicknesses of the vials and/or stoppers can be increased orotherwise adjusted in order to provide an improved or otherwise adjustedMVT barrier. Alternatively, or in conjunction with such measures, theblend of components forming the thermoplastic compounds may be changedas desired to meet desired sorption levels with the particularproduct(s) to be contained within the vial, and/or to achieve desiredMVT characteristics. Still further, in those embodiments of theresealable stopper of the present invention employing multiple layers offusible and infusible materials, the relative thicknesses of thedifferent materials can be adjusted to, in turn, adjust the MVTcharacteristics of the stopper. In addition, as described further below,a tamper-resistant or other cover, that may include a frangible or likeportion that is removable immediately prior to use of the vial to exposethe resealable stopper, can form a hermetic or gas-tight seal betweenthe needle penetrable surface of the stopper and the ambient atmosphere,to further improve the MVT barrier to medicament or other substancecontained within the vial. As also may be recognized by those ofordinary skill in the pertinent art based on the teachings herein, theabove-mentioned numbers and materials are only exemplary, and may bechanged as desired or otherwise required in a particular system.

[0114] Referring now to FIGS. 14A through 14C, a further embodiment ofan assembled medicament vial constructed in accordance with theinventive aspects of the present disclosure is designated generally byreference numeral 300. Vial assembly 300 includes, among other things, astorage vial 310, a stopper member 330, a securing ring 350 and a heatresealable disc 370.

[0115] Storage vial 310 includes a body 312, a base 314 and a neck 316.Body 312 defines an interior chamber 318 that is adapted for storing apredetermined medicament or other substance to be contained therein. Asshown herein, body 312 is substantially cylindrical in shape. However,those skilled in the art would readily appreciate that body 312 can bespherical or any other shape conducive to defining an interior chambersuitable for the storage of medicaments or other substances. Neck 316 isassociated with the top of body 312 and defines a vial mouth 320. In thecurrently preferred embodiments, medicament flow into and out of theinterior chamber 318 is through a needle (both directions).

[0116] Stopper member 330 is inserted into mouth 320 and includes anouter peripheral surface 332 which is adapted and configured forinsertion into mouth 320 and for engagement with neck 316 of storagevial 310. The stopper member 330 provides a first primary seal forcontaining the predetermined medicament within the interior chamber 318of storage vial 310. Stopper member 330 may be formed of vulcanizedrubber. However, those skilled in the art to which this applicationappertains would readily appreciate that other suitable materials may beused for stopper member 330.

[0117] Heat-resealable portion 370 is also inserted into the mouth 320of storage vial 310 and preferably completely overlies stopper member330. As described above with respect to the other embodiments of theresealable stopper, heat-resealable portion 370 is preferably made of aresilient polymeric material, such as a blend of a first polymericmaterial sold by Shell Oil Co. under the registered trademark KRATON® orDYNAFLEX®, and a second material in the form of a low-densitypolyethylene, such as the polyethylene sold by Dow Chemical Co. underthe trademarks ENGAGE™ or EXACT™. In one embodiment, the first andsecond materials are blended within a range of about 50:50 by weight toabout 90:10 by weight (i.e., first material:second material). In anotherembodiment, the blend of the first and second materials is about 50:50by weight. The benefits of the preferred blend over the first materialby itself are improved water or vapor barrier properties, and thusimproved product shelf life; improved heat sealability; a reducedcoefficient of friction; improved moldability or mold flow rates; and areduction in hysteresis losses. As may be recognized by those skilled inthe pertinent art, these numbers and materials are only exemplary,however, and may be changed if desired or otherwise required in aparticular system.

[0118] An important feature of the heat-resealable portion 370 is thatit can be resealed to form a gas-tight seal after inserting a needle,syringe or like injection member therethrough. Preferably, theresealable portion can be sealed by heating the area punctured by theneedle in the manner described above. One advantage of the blendedpolymer described above is that it minimizes the degree to which themedicament can be absorbed into the polymer in comparison to eitherKRATON® or DYNAFLEX® itself.

[0119] With continuing reference to FIGS. 14A through 14C, securing ring350 is shown engaged with the neck 316 of the vial 300 and is adaptedand configured for retaining the heat-resealable portion 370 and thestopper member 330 within the vial mouth 320 and effectuating a secondseal. The securing ring 350 is formed preferably from at least one of athermoplastic and elastic material. The securing ring can be formed froma resilient polymeric material and a low-density polyethylene, similarto that used in the heat-resealable portion 370. Preferably, thesecuring ring 350 is formed by inserting the storage vial 310/stoppermember 330 assembly into a molding apparatus and then molding thesecuring ring material directly over a portion of the storage vial 310and stopper member 330 (referred to as “over-molding”).

[0120] As noted above, it is difficult to maintain the sterility of capsand vials during the transportation, storage and assembly process. Theuse of a non-metallic material for securing ring 350 allows the vial andcap to be assembled and then sterilized as a unit prior to filling thevial assembly with medicament by using, for example, a gammasterilization technique or other irradiation or sterilization process.Unlike threaded plastic caps, an over-molded securing ring provides amechanism for ensuring that the vial has not been compromised andprevents the stopper from being removed.

[0121] As shown in FIG. 14b, securing ring 350 defines a somewhatC-shaped cross-section having a web 356 that separates a lower flange352 and an upper flange 354. The securing ring 350 is formed so thatlower flange 352 is engaged with shoulder 322 of storage vial 310.Additionally, upper flange 354 partially overlies stopper member 330 andheat-resealable portion 370 and thereby secures these elements withinthe mouth 320 of vial body 310.

[0122] During the over-molding process, if desired, the material used toform the securing ring 370 can be provided to the mold at a temperaturethat is sufficient to partially melt in the region of interface of theneck 316 of the vial and/or the heat-resealable disc 370 or stoppermember 330. As a result, upon the cooling of the materials, the securingring 370 is effectively fused with the neck 316 of the vial and/or theheat-resealable portion 370 or stopper member 330. The fusing of thematerials further enhances the sealing and retaining function ofsecuring ring 350. Partial fusion of one or more of the elements asdescribed also is advantageous in vials having a relatively largediameter mouth, since the insertion of a needle into a stopper tends topush the stopper into the interior chamber. If necessary, the fusing ofthe securing ring with the stopper or heat-resealable portion mayfacilitate preventing the collapse of the stopper. It should be notedthat the fusion of the materials can be accomplished by ultrasonicwelding, by applying thermal energy or by using any other knowntechnique for joining thermoplastics, elastics or other materialsemployed.

[0123] It is presently envisioned that in an alternate embodiment, theheat-resealable disc can be removed and the securing ring can be formedso that it completely overlies the stopper member. In this embodiment,the securing ring could be formed of heat-resealable material that isthe same as or similar to that described for disc 370 or otherwisedescribed above. In operation, the stopper member and the securing ringwould be penetrable by a needle or like filling member for theintroduction of medicament into the interior chamber of the vial. Uponwithdrawal of the filling needle, thermal energy would be applied to thesecuring ring for hermetically sealing any hole created by the fillingneedle.

[0124] With continuing reference to FIGS. 14A through 14C, vial assembly300 further includes a peel back cover 380. Cover 380 is adhered tosealing ring 350 subsequent to the filling and resealing processes andprovides a tamper-proof seal which signifies whether medicament has beenwithdrawn or the vial tampered with subsequent to the filling processand vial storage. In addition, if necessary or otherwise desired, thepeel back cover can provide a further barrier to moisture and/or vaportransmission into or out of the interior of the vial.

[0125] As shown in FIG. 14A, the vial 310 defines a spool-like ordiabolo shape. More specifically, the upper portion or securing ring 350defines a first laterally-extending dimension or diameter “D1”, the vialbody 312 defines a second laterally-extending dimension or diameter“D2”, and the base 314 defines a third laterally extending dimension ordiameter “D3”. As can be seen, both D1 and D3 are greater than D2, thusforming a diabolo or spool-like shape. As described above, this shapefacilitates handling during use by permitting the user to grasp thereduced diameter D2 of the vial body with, for example, an index fingerand thumb of one hand. The relatively larger diameter D1 of the upperportion and relatively larger diameter D3 of the base facilitate auser's ability to secure the vial against axial movement. Further, therelatively larger diameter D1 of the upper portion facilitates inpreventing needle sticks by guarding a user's fingers in the event theneedle slips or otherwise misses the stopper. In addition, as describedfurther below, the diabolo or spool-like shape can cause the vial todefine a lower center of gravity than other prior art vials, and thusbetter prevent tipping of the vial during handling in, for example, anautomated filling machine. As also described further below, the diaboloor spool-like shape facilitates in securing and otherwise handling thevial during automated sterilization, needle filling and/or thermalresealing of the vial.

[0126] Referring now to FIG. 15, another vial assembly constructed inaccordance with a representative embodiment of the present disclosure isdesignated generally by reference numeral 400. Vial assembly 400includes, among other things, a storage vial 410, a stopper member 430,and a securing ring 450. Storage vial 410 has a cylindrical body 412which interconnects a base 414 and a neck 416. The body 412 has an outerwall 411 that defines an interior chamber 418 for storing apredetermined medicament and a central axis 413 for vial assembly 400.

[0127] Unlike vial 300, in which base 314 and body 312 are formed as aunit, the base 414 and the body 412 of storage vial 410 are formedindependently. Base 414 includes an inner surface 422 which is adaptedand configured for engagement with an axially depending flange 424 ofstorage vial 410. The base 414 can be engaged with the body 412 by meansof a press-fit relationship, adhesion, ultrasonic welding or any otherjoining technique. Due to its width, and as with the base of the vial300 as described above, the base 414 increases the vertical stability ofvial assembly 400 when placed on a horizontal surface.

[0128] With continuing reference to FIG. 15, in the embodiment shownherein, stopper member 430 has an annular groove 434 defined in outerperiphery 432. When stopper member 430 is inserted into the mouth 420 ofstorage vial 410, an annular recess is formed between stopper member 430and the neck 416 of storage vial 410. Securing ring 450 is formed inthis recess preferably in the manner hereinafter described.

[0129] Referring now to FIGS. 16A and 16B, a representative process forforming securing ring 450 is illustrated. As shown in FIG. 16A, vialbody 412 is first placed within a cavity defined by lower mold assembly460. For ease in manufacturing, base 414 has not yet been engaged withflange 424 of vial body 412. Mold assembly 460 includes a bottom 462 andfirst and second sidewalls 464 and 466, respectively.

[0130] Stopper member 430 is then inserted into the mouth of vial body412. As noted above with respect to FIG. 15, stopper member 430 has anannular groove 434 defined in its outer periphery 432. When stoppermember 430 is inserted into the mouth of vial body 412, an annularrecess is formed between stopper member 430 and the neck 416 of storagevial 410. Alternatively, to reduce the potential for particulatecontamination, vial body 412 and stopper member 430 can be formed inside-by-side molds in a clean room environment. The stopper member 430can be inserted into the mouth of the vial body 412 prior to thetransfer out of the clean room environment and to mold assembly 460thereby preventing particulate from accumulating in the interior chamber418.

[0131] Next, as shown in FIG. 16b, upper mold element 468 is positionedover lower mold assembly 460. Securing ring 450 is then formed byinjecting (indicated by the flow arrows) at least one of a thermoplasticand elastic material in liquefied form into the annular recess. Duringthe molding process, and when the vial body is formed of a plasticmaterial (as opposed to glass, for example) the temperature of thematerial used to form securing ring 450 is sufficient to partially melton contact the adjacent material of neck 416. Therefore, upon cooling,securing ring 450 is partially fused with neck 416 so as to retainstopper member 430 within the vial mouth. It should be noted that thefusion can be achieved by ultrasonic welding, by applying thermal energyor by any other known technique for joining thermoplastics, elastics, orother materials employed.

[0132] A closure for a vial manufactured in accordance with the methoddetailed in FIGS. 16A and 16B includes a sealing ring formed byinjecting liquefied ENGAGE™ polyolefin into the annular recess definedbetween the stopper and the vial neck at a temperature in excess ofabout 390° F. The stopper is made from a thermoplastic comprising ablend of ENGAGE™ and DYNAFLEX™ in the manner described above. Thetemperature of the liquefied ENGAGE™ is sufficient to locally melt thethermoplastic stopper as well as the vial neck. Upon cooling of thematerials, air may be supplied to the interior chamber through anaperture drilled or otherwise formed in the bottom of the vial body.Applicant has determined that the interior chamber may be pressurized inexcess of about 80 psi without dislodging the closure formed by thestopper and securing ring from within the vial mouth.

[0133] Referring now to FIGS. 17A through 17C, a representative processfor making a vial assembly in accordance with the present disclosure isillustrated. Vial assembly 500 includes a storage vial 510, anover-molded stopper 530 and an over-molded base 580. Storage vial 510 isstructurally similar to storage vials 310 and 410 described above,except that storage vial 510 has both an open top and an open bottomend.

[0134] As with the vial 310 described above, and as shown in FIG. 15,the vial 410 defines a diabolo or spool-like shape formed by therelatively larger diameters D1 of the upper portion 417 and D3 of thebase 415, and the relatively smaller diameter D2 of the body 412extending axially between the upper portion and base.

[0135] As shown in FIG. 17A, storage vial 510 is first positioned withina cavity partially defined by mold assembly 560. Mold assembly 560includes bottom portion 562, first and second sidewalls 564 and 566,respectively, and upper portion 568. Bottom portion 562 of mold assembly560 has a cylindrical mold insert 570 projecting therefrom and intostorage vial 510. An upper surface 572 of mold insert 570 is adapted andconfigured for defining a lower surface for over-molded stopper 530.Over-molded stopper 530 is formed by injecting at least one of athermoplastic and elastic material in liquefied form into the cavitydefined by the molding elements.

[0136] Upon the formation of stopper 530, the vial body 510 withover-molded stopper 530 is removed from the mold. As shown in FIG. 17B,a base member 514 is engaged with the bottom of storage vial 510 by anyof the methods described above. Lastly, the assembled vial is positionedwithin a second mold assembly (not shown) and an over-molded base 580 isformed in a manner similar to the previously described over-moldingprocess.

[0137] Referring now to FIG. 18, another vial assembly constructed inaccordance with a representative embodiment of the present disclosure isdesignated generally by reference numeral 600. Similarly to thepreviously described embodiments, vial assembly 600 includes a storagevial 610 and a stopper member 630. Storage vial 610 has a cylindricalbody 612, a snap-on base 614 and a neck 616. Body 612 defines aninterior chamber 618 for storing a predetermined medicament and acentral axis for vial assembly 600.

[0138] As described above, stopper member 630 includes an outerperipheral surface 632 which is adapted and configured for engagementwith the neck 616 of storage vial 610. Peripheral surface 632 of stoppermember 630 provides a first primary seal for containing thepredetermined medicament within the interior chamber of vial body. Ascan be seen, the neck 616 of the vial defines a pointed annularprotuberance 617 that projects axially into the overlying stoppermaterial to thereby further effectuate a hermetic seal between thestopper and vial. In contrast to the previously described embodiments,vial assembly 600 further includes a locking or securing ring or lockingring 650 and a snap-off, tamper-resistant cover 640. Locking ring 650has an outer peripheral flange 652 that defines a shoulder 654 on aninner surface thereof. Shoulder 654 is adapted and configured forinterlocking engagement with lower surface 620 of neck 614. Locking ring650 is made from a relatively flexible, non-metallic material, such asplastic.

[0139] During the assembly process, locking ring 650 is positioned overstopper member 630. Locking ring 650 is pressed axially downward so asto compress and retain stopper member 630 within the mouth of the vial.The flexibility and configuration of flange 652 of the locking ringallows the flange to flex radially outward of outer peripheral surface622 of neck 614. Once shoulder 654 passes axially downward beyond lowersurface 620, the flange 652 flexes back and shoulder 654 and lowersurface 620 form a snap-fit, interlocking engagement. In arepresentative embodiment, an annular recess is scored or otherwiseformed in the outer surface of flange 652 after the locking ring 650 isengaged with neck 614 of storage vial 610. As can be seen, locking ring650 can not be disengaged from neck 614 without breaking flange 652.This feature functions to prevent removal of the stopper and anytampering with the contents of the vial without piercing the stopper.

[0140] Locking ring 650 defines a central aperture that allows stoppermember 630 to be accessed therethrough by a needle or like device.Tamper-resistant cover 640 is configured to overlie the central apertureof locking ring 650 and engage with locking ring 650, thereby protectingthe exposed stopper material. In the embodiment shown herein, cover 640is engaged with locking ring 650 by means of a press-fit similar to thatpreviously described for the locking ring 650. Cover 640 includes anouter peripheral flange 642 that defines a shoulder 655 on an innerdiameter thereof which is adapted for interlocking engagement withperipheral recess 656 associated with locking ring 650. Tamper-resistantcover 640 further defines on its underside a pointed annularprotuberance 657 that is pressed into engagement with the adjacentstopper material to thereby effectuate a hermetic seal between the cover640 and stopper 630. Preferably, tamper-resistant cover 640 cannot beremoved from the vial without breaking the cover, thus providing afurther tamper-resistant feature. Alternatively, this tamper-resistantfeature can be created by using ultrasonic welding, adhesion, or anyother connection technique to engage tamper-resistant cover 640 withlocking ring 650 so that once removed, cover 640 can not be re-engagedwith locking ring 650.

[0141] As may be recognized by those of ordinary skill in the pertinentart based on the teachings herein, the vial may be made of glass,plastic, or a combination of glass and plastic. For example, the vialbody may be made of glass, whereas the base 614 may be made of plastic,and the locking ring 650 and tamper-resistant ring may be made ofplastic. The plastic base and locking ring may be attached to the glassvial body in any of the numerous different ways described herein,including by over-molding the plastic component onto the glasscomponent, by mechanical snap-fit or other interlocking engagementbetween the plastic component and the glass component, or by adhesivelyjoining the plastic component to the glass component. In addition, inthis embodiment of the invention, the stopper may include a vulcanizedrubber or other infusible base portion, and a thermoplastic or otherthermally fusible portion overlying the base portion that is thermallyfusible in the manner described above. One advantage of this type ofembodiment of the present invention, is that the medicament or othersubstance contained within the vial is exposed to, or stored in contactwith only the glass and vulcanized rubber surfaces. Thus, this type ofembodiment may be easily used with medicaments or other substances thatare were in the past stored in glass vials with vulcanized rubber orlike stoppers.

[0142] In FIGS. 22A, 22B and 22C, the cover 640 is illustrated infurther detail and includes a frangible portion 660 connected to theremainder of the cover by a plurality of radially-spaced frangibleconnections 662. As can be seen, in order to access the resealablestopper 630 with a needle or like device, the frangible portion 660 mustbe flipped away from the stopper with sufficient force to break thefrangible connections 662 and thus permit release of the frangibleportion 660 therefrom. As can be seen, the cover 640 may define aperipheral rim 664 that is engageable by a user's thumb, for example, topress and, in turn, break away the frangible portion 660. Once thefrangible connections 662 are broken, the frangible portion 660 cannotbe reattached, thus providing a tamper-proof feature. In addition, theannular protuberance 657 and associated portion of the cover overlyingthe stopper material within the central aperture of the locking ring 650further seals the stopper and interior portions of the vial from theambient atmosphere, and thus further prevents the exposure of ambientgases, vapors or other unwanted substances to either the stopper or thesubstances contained within the vial. For example, the cover 640 cansignificantly improve the vapor (or MVT) barrier provided by the stopperassembly and thereby increase the effective shelf-life of the substancescontained within the vial.

[0143] One of the advantages associated with the vial assembly 600, aswell as vial assemblies 300, 400, and 500, is that they are configuredto be spool-shaped or diabolo-shaped. As described above, the upper andlower portions of the vial assemblies have outer peripheral surfaceswhich are positioned radially outward of the central vial body. As aresult, during the withdrawal of the medicament by the healthcareworker, the fingers that grasp the recessed vial body are protected andare less likely to be pierced by a needle that has slipped off of thestopper.

[0144] Configuring the vial assembly so as to be diabolo-shaped alsoimproves the stability of the filled vials, as well as the handling ofthe vials during the sterilization and filling processes. A vial with abase that has an outer peripheral surface positioned radially outward ofthe central vial body has a lower center of gravity than a traditionalblow molded vial of the same height with a base that does not protruderadially from the vial body. The protrusion of the upper and lowerportions beyond the outer diameter of the vial body also improves thehandling of the vial body or assembly by providing upper and lowershoulders which can be used to guide the vial during the handlingprocess and facilitate the use of automated handling equipment (e.g.,pick and place robotics).

[0145] A further advantage of the vial assemblies described herein isthat the tamper-resistant covers may be hermetically sealed to theunderlying locking members and/or the resealable stoppers to therebyseal the stoppers within the locking members and covers and with respectto the ambient atmosphere. In accordance with one aspect of a preferredembodiment of the present invention, the overlying locking members andcovers can be formed of relatively rigid materials and/or of materialshaving relatively high resistances to moisture and vapor transmission incomparison to the material of the resealable stopper itself, in order tofacilitate preventing the loss of any medicament or other substancecontained within the vial or other container therethrough, or theingress of moisture or vapor into the vial or other container, during,for example, storage, transportation and/or product shelf life.

[0146] With reference to FIGS. 19 through 21, there is illustratedanother vial assembly 700 constructed in accordance with inventiveaspects of the present disclosure. Vial assembly 700 includes, amongother features, a closure assembly 735 and a vial body 710. Similar tothe closure assembly of FIG. 18, closure assembly 735 is a three-pieceassembly comprising a stopper member 730, a locking or securing ring orcap 750 and a tamper-resistant cover 740.

[0147] Unlike the closure assembly of FIG. 18, closure assembly 735 isformed partially by a sequential molding process. More specifically, thestopper 730 (FIG. 20) and the locking ring 750 are formed as a unit by atwo-step molding process. The stopper 730 is first fabricated by anyknown molding process. As shown in FIG. 20, the outer periphery 732 ofstopper 730 includes an annular recess 736. Stopper 730 is then placedin a mold assembly and is used to define at least a portion of the innersurface 752 of locking ring 750. A thermoplastic or elastic is injectedinto the mold so as to form locking ring 750 having an annularprotrusion 754 that is engaged within the annular recess 736 of stopper730. Then, as shown in FIG. 19, the unitized stopper/locking ring isengaged with the open end of vial body 710 so as to seal interior cavity718.

[0148] Locking ring 750 includes an annular groove 756 formed along itsouter periphery. As shown in FIG. 19, tamper-resistant cover 740includes an outer peripheral flange 744 depending therefrom. Flange 744is slidably engaged within groove 756 of locking ring 750 and securescover 740 to locking ring 750. When the tamper-resistant cover 740 ispressed into engagement with locking ring 750, annular rib 738 ofstopper 730 is compressed by the bottom of the cover and a secondhermetic seal is thereby formed. Accordingly, the tamper-resistant cover740 forms a hermetic or gas-tight seal between the exterior surface ofthe stopper and the ambient atmosphere, thereby providing a further MVTbarrier between the interior of the vial and the ambient atmosphere. Asmay be recognized by those of ordinary skill in the pertinent art basedon the teachings herein, the material(s) and/or thickness of thetamper-resistant cover 740 and/or of the locking ring 750, or at leastthe portion(s) of the cover and/or locking ring that overly and seal theexposed surface(s) of the stopper, may be selected to control the MVTbarrier between the interior and exterior of the vial in the directionthrough the stopper.

[0149] The annular groove 756 formed along the outer periphery oflocking ring 750 also functions to reduce the likelihood of anaccidental needle stick. In order to access stopper 730, for the purposeof removing medicament from within interior chamber 718, cover 740 isdisengaged from locking ring 750 exposing groove 756. If by chance theneedle being used to withdraw the medicament accidentally slips off ofor relative to the stopper 730, the needle will likely slide intoannular groove 756 rather than continue in a downward trajectory andpotentially pierce the hand of the healthcare worker.

[0150] With continuing reference to FIGS. 19 and 20, cavity 734, whichis defined in the bottom of stopper 730, allows the upper portion of thestopper 730 to flex upon the application of force to annular rib 738 bycover 740. As a result, the lower portion of the stopper member isforced radially outward and the circumferential seal created between theouter periphery 732 of the stopper 730 and the vial body 710 isimproved. Additionally, the upper portion of stopper 730 is radiallycompressed as a result of the forces applied to annular rib 738, forminga hermetic or gas-tight seal between the tamper-resistant cover 740 andthe exposed surface of the stopper to thereby further seal the stopperfrom the ambient atmosphere and, if desired, further improve the MVTbarrier between the interior of the vial and the ambient atmosphere.

[0151] In FIGS. 23 through 28, another vial embodying the presentinvention is indicated generally by the reference numeral 800. The vial800 is similar in many respects to the vials described above withreference to FIGS. 14 through 23, and therefore like reference numeralspreceded by the numeral “8” are used to indicate like elements. Theprimary difference of the vial 800 in comparison to the vials describedabove is that the locking ring 850 is welded, such as by ultrasonicwelding, to the neck 816 of the vial body. In addition, the flip-top ortamper-resistant cover 840 is tack welded, such as by ultrasonicwelding, to the locking ring 850. As shown in FIGS. 24 and 28, thestopper 830 defines an annular flange 832, the neck 816 of the vial bodydefines a pointed annular protuberance 817 that projects into one sideof the stopper flange 832, and the locking ring 850 defines anotherannular protuberance 819 that projects into the opposite side of thestopper flange 832. Thus, the annular protuberances 817 and 819 definecontinuous, annular sealing surfaces that facilitate in effectuating agas-tight or hermetic seal between the stopper and vial body. Further,as shown in FIG. 24, the peripheral surface 832 forms an interferencefit with the interior of the valve body 810 to further effectuate agas-tight or hermetic seal between the stopper and vial body. The neck816 defines on its axial face a pointed annular protuberance 821 that isreceived within a corresponding annular recess 823 defined in theunderside of the locking ring 850. The annular protuberance 821 is fusedto the locking ring 850 within the annular recess 823 by ultrasonicwelding, for example, to thereby fixedly secure the locking ring to thevial body. In addition, the annular weld preferably defines a hermeticor gas-tight seal between the locking ring and vial body to furthereffectuate a gas-tight or hermetic seal between the interior of the vialand the ambient atmosphere. The locking ring 850 further defines on itsdistal end a plurality of discrete radially-extending protuberances 866received within corresponding recesses 868 formed within the undersideof the locking ring 840. The protuberances 866 are fused to the cover840 within the recesses 868 by, for example, ultrasonic welding, tothereby define a plurality of frangible connections between the cover840 and locking ring 850. Alternatively, as shown in FIG. 27,protuberances 866′ may be formed at the base of the flange 842 of thecover and may be fused within corresponding recesses 868′ formed withinthe annular recess 870 of the locking ring. As also shown in FIGS. 24,27 and 28, the base of the vial body defines a pointed annularprotuberance 815 that is received within a corresponding annular recessformed in the base 814 for fixedly securing the base to the body, suchas, for example, by ultrasonic welding.

[0152] In order to fill the vial 810, the stopper 830, locking ring 850,and base 814 are assembled to the empty vial body, such as by ultrasonicwelding. Then, the empty vial is sterilized, such as by the applicationof gamma or other type of radiation thereto. Then, the sterilized, emptyvials are needle filled and thermally resealed, such as by laserresealing as described above. Then, the tamper-resistant cover 840 isassembled to the filled vial by fixedly securing the cover to thelocking ring 850, such as by ultrasonic welding as described above. Asshown typically in FIG. 24, the exterior surface of the stopper 830 mayform an interference fit with the interior surface of thetamper-resistant cover to further effectuate a gas-tight or hermeticseal between the cover and stopper to, in turn, form a further MVTbarrier between the interior of the vial and the ambient atmospherethrough the cover. If desired, a peripheral seal may be formed betweenfrusto-conical portion 870 of the locking ring and the underside of thetamper-resistant cover 840 by forming an annular seal at 866,868 by, forexample, ultrasonic welding, to form the hermetic or gas-tight sealbetween the stopper and the ambient atmosphere and, in turn, form thedesired MVT barrier. In order to use the vial, the tamper-resistantcover 840 is removed by gripping with, for example, a thumb, theperipheral edge 843 of the cover, and pushing the cover upwardly orsubstantially axially away from the locking ring to, in turn, break thefrangible connections 866, 868 or 866′, 868′ and release the cover, or afrangible portion thereof, from the locking ring to expose theunderlying stopper. As may be recognized by those of ordinary skill inthe pertinent art based on the teachings herein, the tamper-resistantcover and/or the frangible portion thereof may taken any of numerousdifferent shapes and/or configurations that are currently or laterbecome known for performing the function of the tamper-resistant coveras described herein.

[0153] In FIGS. 29 through 31, another vial embodying the presentinvention is indicated generally by the reference numeral 900. The vial900 is similar in many respects to the vials described above withreference to FIGS. 14 through 28, and therefore like reference numeralspreceded by the numeral “9” are used to indicate like elements. Theprimary difference of the vial 900 in comparison to the vials describedabove is that the locking ring 950 is snap-fit to the vial body 910, andthe locking ring 950 defines the neck 916 of the vial. As can be seen,the locking ring 950 defines a peripheral flange forming the neck 916and further defines on its interior edge an annular recess 968 forreceiving therein an annular protuberance 966 formed on thetamper-resistant cover 940. As can be seen, the interior edge of theannular flange 916 leading into the recess 968 defines a chamferedsurface, and the leading edge of the annular protuberance 966 of thecover also is chamfered to allow the protuberance to be snapped into, orotherwise fixedly received within the recess, but to prevent removal ofthe cover therefrom. Similarly, the locking ring 950 defines on itsinner diameter an annular protuberance 921 that is snapped into, orotherwise fixedly received within a corresponding annular recess 923formed on the exterior of the vial body to fixedly secure the cover tothe vial body. In this embodiment, the base 914 of the vial body isformed integral with the remainder of the vial body in order to reducethe number of parts; however, if desired, the base 914 can be made as aseparate part that is snap-fit or otherwise attached to the vial body.

[0154] As shown typically in FIG. 31, the tamper-resistant cover 940defines a centrally-located frangible portion 960, an inwardly dependingannular protuberance 963 that engages the exposed surface of the stopper930 and forms a hermetic or gas-tight seal therebetween, and afrusto-conical portion 965 that is formed on its outer end contiguous tothe annular protuberance 963 and preferably forms a gas-tight orhermetic seal therebetween. As shown in FIGS. 30 and 31, a plurality offrangible connections 962 are angularly spaced relative to each otherand extend between the frangible portion 960 and a substantiallydome-shaped cover body 941 to allow removal of the frangible portion andaccess to the underlying stopper 930. As indicated by the arrow in FIG.32, the frangible portion 960 of the cover is pressed downwardly by, forexample, a user's finger to slightly depress the underlying stoppermaterial and, in turn, break the frangible connections 962. Onceremoved, the frangible portion 960 cannot be reconnected to therebyprovide a tamper-proof feature. Thus, prior to removing the frangibleportion 960 of the tamper-resistant cover 940, the frangible portion960, along with its annular protuberance 963, and the frusto-conicalportion 965 of the locking ring 950, form a substantially gas-tight orhermetic seal between the stopper and ambient atmosphere, and thusprovide a further MVT barrier between the interior of the vial andambient atmosphere in the direction through the stopper. If desired, orotherwise deemed necessary to further obtain a desired MVT barrier, thefrusto-conical portion 965 and peripheral flange 916 may form acontinuous solid barrier, as indicated in broken lines in FIG. 29 (i.e.,without any openings), to completely seal the stopper from the ambientatmosphere.

[0155] Turning to FIGS. 32 through 36, a plurality of the diabolo shapedvials 610 of the present invention are shown mounted within a sterilefilling machine that needle fills and laser reseals the vials asdisclosed in co-pending U.S. Provisional Patent Application Serial No.60/484,204, filed Jun. 30, 2004, and incorporated by reference above. Ascan be seen, each vial 610 does not include the tamper-resistant cover640 (FIG. 18) during the needle filling and laser resealing process, butrather the tamper-resistant covers are secured to the vials after needlefilling and laser resealing. As may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, although thevials 610 are shown mounted within the sterile filling machine, any ofthe other vials described herein or otherwise embodying the features ofthe invention equally may be filled and sealed in the illustratedsterile filling machine. The sterile filling machine includes a sterileenclosure (not shown), a laminar flow source (not shown) that provides asubstantially laminar flow of sterile air of other gas over the vialsbeing transported within the enclosure, and as shown in FIGS. 33-36, atransport system comprising in the illustrated embodiment a plurality ofstar wheels 1010, and associated guides 1012 spaced adjacent to theperiphery of each star wheel 1010 for supporting the vials 610therebetween.

[0156] As shown in FIGS. 33-36, each of the star wheels 1010 has aplurality of recesses 1014 along its peripheral surface that are adaptedto receive the mid-portions of the vials 610. One or more of the starwheels may have a saw-tooth like periphery that reduces the likelihoodof jamming against vials as they are received, for example, from aturntable and infeed channel into the star wheels. In such embodiment,the periphery of the star wheel defines a plurality of teeth, whereineach tooth has a pointed end, and each two successive teeth form arespective one of the recesses adapted to receive a vial. In thisembodiment, the teeth and/or recesses are shaped and/or dimensioned suchthat the portion of the tooth that is substantially upstream andadjacent to the point defines a seat in which a respective vial rests.Also in this embodiment, the seat defines a surface that pushes againstthe container. Other designs may of course also be employed. If desired,the recesses 1014 of one or more star wheels may be provided with vacuumports which are selectively connected to a vacuum source (not shown) tothereby allow the star wheels to carry and release vials as appropriate.

[0157] As shown best in FIGS. 32-35, a needle fill manifold 1016 isdisposed at a first position along the periphery of the star wheel 1010in a needle filling station of the sterile filling machine. The needlefill manifold 1016 holds a plurality of needles, e.g., four needles1018, 1020, 1022 and 1024, which are used to deliver medicament or othersubstances into the sealed vials. The needle manifold 1016 is drivinglymounted such that each needle is movable into and out of engagement withthe resealable stoppers to pierce the stoppers and fill the vials with amedicament or other substance to be contained therein, and to thenwithdraw the needle upon filling the vial. Providing multiple needlesmakes it possible to fill multiple vials concurrently. Each of theneedles is in flow communication with a respective flexible tube 1026,1028, 1030 and 1032 that connects the respective needle 1018, 1020, 1022and 1024 to a respective medicament or other substance source (notshown) through a respective one of a plurality of pumps (not shown). Themedicament source may be located inside the filling machine or outsideof the filling machine.

[0158] As shown in FIGS. 33-35, the needle fill manifold 1016 is mountedon a pair drive shafts 1034 that are drivingly connected to a suitabledrive source (not shown) driving the needle manifold, and thus the bankof needles mounted on the manifold, into and out of engagement with theresealable stoppers of the vials mounted in the needle filling station,as indicated by the arrow “a” shown typically in FIG. 33. Although notshown, a bellows may encase the base of each shaft to seal the movableparts of the shafts. As shown best in FIG. 32, the needle manifold 1016further includes a base 1036, a plurality of needle mounts 1038 spacedrelative to each other and defining laminar flow apertures 1040therebetween, and a clamp 1042 that is fixedly secured by fasteners 1044(FIG. 33) to the base 1036 to, in turn, secure the needles to themanifold. As shown in FIG. 32, each needle includes a mounting flange1046 that is slidably received within an aperture formed in therespective needle mount 1038, and is fixed in place upon securing theclamp 1042 to the base 1036. Alignment pins 1048 project outwardly fromthe front face of the base 1036 and are received within correspondingapertures formed in the clamp 1042 to ensure proper alignment of theclamp and needles on the manifold. As shown in FIG. 35, the a mountingplate 1050 is fixedly secured to the ends of the drive shafts 1034, 1034and is movable therewith. Alignment pins (not shown) extend between thebase 1036 of the needle manifold 1016 and the drive plate 1050 to ensureproper alignment of the needle manifold, and thus the needles, on thedrive plate. A pair of thumb screws 1052 are threadedly received throughopposite ends of the base 1036 of the manifold to releasably secure themanifold to the drive plate 1050. As shown in FIG. 36, a laser sealingand infrared (IR) sense manifold 1054 is disposed at a second positionalong the periphery of the star wheel 1010, downstream of the needlefill manifold 1016. As shown typically in FIG. 36, the laser sealing andinfrared (IR) sense manifold 1054 holds a plurality of laser opticsassemblies (e.g., four laser optic assemblies 1056, 1058, 1060 and1062), along with a plurality of IR sensors (e.g., four IR sensors 1064,1066, 1068 and 1070). The laser optic assemblies are adapted to providea laser beam to reseal the resealable stoppers on the vials after needlefilling. Each of the plurality of laser optic assemblies is mounted at arespective location near the periphery of the star wheel 1010 fortransmitting a respective laser beam onto a respective resealablestopper to heat seal the needle aperture in the resealable stopper. Eachof the laser optic assemblies 1056, 1058, 1060 and 1062 is connected toa respective fiber optic cable that connects the respective opticassembly to a respective laser source (not shown). Providing multiplefiber optic assemblies makes it possible to reseal multiple vialsconcurrently. In this embodiment, each of the plurality of IR sensorassemblies 1064-1070 is mounted at a respective location near theperiphery of the star wheel 1010. Preferably, the laser sources (notshown) are mounted outside of the enclosure to enable repair and/orreplacement of the laser sources without having to open the enclosureand/or otherwise risk contamination of the sterile enclosure. The IRsensors 1064-1070 detect the temperature of the needle penetrationregion of the resealable stopper achieved during laser resealing, andtherefore can be used to determine whether the stopper was sufficientlyreheated to achieve resealing. Each of the IR sensors 1064-1070 isconnected to a respective IR sensor module (not shown). Providingmultiple IR sensors enables the sterile filling machine to sense thetemperature of multiple vials concurrently, for example, as they arebeing resealed.

[0159] As described above, each laser source transmits a predeterminedwavelength of laser radiation at about 980 nm, and the predeterminedpower of each laser is preferably less than about 30 Watts, andpreferably less than or equal to about 10 Watts, or within the range ofabout 8 to about 10 Watts. In the illustrated embodiment, each lasersource is a semi-conductor diode laser that outputs at about 15 Watts,and is fiber-optically coupled through a fiber-optic cable to respectivecollimating lens mounted over the vials within the interior of thefilling unit. The laser and IR sensor manifold 1054 includes a tintedenclosure 1072 including a plurality of tinted glass or translucent ortransparent plastic panels that surround the lasers on four sides tofilter out potentially harmful radiation generated by the laser beams.Capacitor sensors (not shown) also may be provided along the peripheryof the star wheel 1010, downstream of the needle fill manifold 1016 inorder to sense whether each vial received the medicament or othersubstance to be contained therein and to reject the vial if defective.

[0160] In the operation of the sterile filling machine, the star wheel1010 transports the vials 610 along the guide 1012 in the mannerillustrated. The star wheel 1012 is indexed four positions and thenpaused for a momentary dwell. During the dwell, the needle manifold 1016is driven downward so as to drive the four needles 1018-1024 through theresealable stoppers on the four vials beneath the needle manifold.Medicament or other substance is thereafter delivered by the pumpthrough the needles and into the interior chambers of the vials, and themanifold is then driven up to thereby retract the four needles 1018-1024from the four stoppers. In one embodiment, the needles are initiallywithdrawn at a relatively slow speed to allow the vials to fill“bottom-up”; then, when the vials are filled, the needles are withdrawnat a relatively faster speed to quickly remove the needles and decreasesoverall cycle time. As shown in FIGS. 33-35, the diabolo or spool-likeshape of the vials facilitates the ability to transport the vials on thestar wheels or other conveying system, and further, the diabolo shapesupport the vials and prevents axial movement of the vials duringinsertion and withdrawal of the needles during filling. The mid-portionof each vial is secured within the recess of the star wheel or otherconveying mechanism, the relatively larger diameter upper portion ofeach vial prevents axial downward movement of the vial upon insertingthe needle into the resealable stopper of the vial by engaging the uppersurface of the star wheel and/or guide, and the relatively largerdiameter base portion of the vial prevents upward axial movement of thevial upon withdrawal of the needle from the resealable stopper byengaging the underside of the star wheel and/or guide.

[0161] Also during the dwell, the four laser optic assemblies 1056-1062deliver laser energy to the resealable stoppers on the four vialsbeneath the laser and IR manifold to reseal the stoppers. As theresealable stoppers are heated by the laser energy, the four IR sensors1064-1070 detect the temperature of each stopper, so as to be able todetermine whether each stopper was heated sufficient to cause resealing.After the dwell, the process is repeated, i.e., the star wheels indexanother four positions and then dwell again so that the next four vialsare filled and four more vials are resealed.

[0162] After resealing, the vials are transferred to the another starwheel (not shown), which employs the vacuum ports in its recesses toretain each vial as it is transported. If a vial was successfully filledand sealed, then the star wheel transports that vial until reaching adischarge guide, at which point the vacuum to the associated vacuum portis selectively removed and the vial is transferred to the dischargeguide. The discharge guide transports the vial to a bin (not shown) ofsuccessfully filled and sealed containers. If a vial was notsuccessfully filled and sealed, then the star wheel transports that vialuntil it reaches another star wheel, at which point the vacuum to theassociated vacuum port is selectively removed and vacuum is applied tothe respective vacuum port on the other star wheel, thereby transferringthe vial to the other star wheel for disposal with any other defectivevials.

[0163] In FIGS. 37-48, a module for needle filling and laser resealingthe vials is indicated generally by the reference numeral 2000. Theneedle filling and laser resealing module 2000 is similar in manyrespects to the needle manifold and laser and IR sensor manifolddescribed above, and therefore like reference numerals preceded by thenumeral “2” instead of the numeral “1” are used to indicate likeelements. One of the primary differences of the module 2000 incomparison to the manifolds described above, is that the module 2000permits both needle filling and laser resealing in the same module.Further, if desired, the module 2000 can include an e-beam or othersuitable radiation or sterilization source to further ensuresterilization of the vials and filling needles, as described furtherbelow.

[0164] The module 2000 may be mounted within any of numerous differenttypes of sterile enclosures, and may be used with any of numerousdifferent types of conveying systems for conveying the vials through themodule. If desired, the sterile enclosure may include a laminar flowsource as described in the above-mentioned co-pending patentapplication. Preferably, the transport system through the module issubstantially linear, and includes a guide 2010 defining an axiallyelongated aperture 2014 extending therethrough. As shown in FIGS. 39 and40, the axially extending aperture 2014 is dimensioned to slidablereceive therein the mid-portions of the diabolo-shaped vials, to supporton the upper opposing surfaces of the guide 2010 the relatively largerdiameter upper portion of each vial, and if desired, to support againstthe opposing lower surfaces of the guide the relatively larger diameterbase portion of each vial. In one embodiment of the present inventionillustrated in FIG. 43, the transport system comprises a screw-typedrive including a lead screw 2015 defining a helical groove 2017 formingthe recesses for receiving the vials 610. A motor 2019 is drivinglyconnected to one end of the lead screw and rotatably drives the screw asindicated by the arrow “b” to, in turn, axially drive the vials 610through the manifold 2000. The motor 2019 is electrically connected to acontrol unit (not shown) to precisely control the starting, stopping andspeed of the screw, and to coordinate same with the actuation of theneedle manifold and laser sources. As may be recognized by those ofordinary skill in the pertinent art based on the teachings herein, thetransport system may include any of numerous different structures fordriving the vials through the manifold, including, for example, othertypes of conveyors, that are currently, or later become known, forperforming this function.

[0165] The needle fill manifold 2016 is mounted on a pair drive shafts2034 that are drivingly connected through a common drive shaft 2035(FIG. 42) to a suitable drive source (not shown) for driving the needlemanifold, and thus the bank of needles 2018 (only one shown) mounted onthe manifold, into and out of engagement with the resealable stoppers ofthe vials received within the guide 2010 of the manifold. Although notshown, a bellows may encase the base of each shaft to seal the movableparts of the shafts. The needle manifold 2016 includes a base 2036, aplurality of needle mounts 2038 spaced relative to each other, and aclamp 2042 that is fixedly secured by fasteners (not shown) to the base2036 to, in turn, secure the needles to the manifold. If desired,laminar flow apertures may be formed between the needle mounts 2038 toallow the flow of sterile air or other gas therethrough and over thesides of the needles. Each needle includes a mounting flange 2046 thatis slidably received within an aperture formed in the respective needlemount 2038, and is fixed in place upon securing the clamp 2042 to thebase 2036. Providing multiple needles makes it possible to fill multiplevials concurrently. Each of the needles is in flow communication with arespective flexible tube 2026 that connects the respective needle 2018to a respective medicament or other substance source (not shown) througha respective one of a plurality of pumps (not shown). The medicamentsource may be located inside the filling machine or outside of thefilling machine.

[0166] As shown typically in FIG. 41, alignment pins 2039 may beprovided on the clamp 2042 and received within corresponding pin holes2041 formed on the base 2036 to ensure proper alignment of the clamp andneedles on the manifold. A mounting plate 2050 is fixedly secured to theends of the drive shafts 2034, 2034 and is movable therewith. The driveplate 2050 defines a mounting surface 2053 that is received withincorresponding mounting grooves 2055 formed within the base 2036 of themanifold to mount and align the manifold on the drive plate. Alignmentpins (not shown) may extend between the base 2036 of the needle manifold2016 and the drive plate 2050 to ensure proper alignment of the needlemanifold, and thus the needles, on the drive plate. A locking clamp 2052is pivotally mounted on the drive plate 2050 and is movable between anopen position to either release the manifold from, or attach themanifold to the drive plate, as shown in FIG. 37, and a closed positionfixedly securing the manifold to the drive plate, as shown in FIG. 38.Alternatively, as shown in FIGS. 40A-40C, fasteners 2052′ may beemployed to secure the manifold to the drive plate, instead of theclamp. As may be recognized by those or ordinary skill in the pertinentart based on the teachings herein, any of numerous different clamps orfastening mechanisms that are currently known, or later become known,equally may be employed to secure the manifold to the drive plate.

[0167] The module 2000 further includes a laser sealing and infrared(IR) sense manifold 2054 that is radially spaced adjacent to the needlemanifold 2036 for laser sealing the pierced stoppers immediatelyfollowing needle filling and withdrawal of the needles therefrom. Asshown typically in FIG. 42, the laser sealing and infrared (IR) sensemanifold 2054 holds a plurality of laser optics assemblies (e.g., fivelaser optic assemblies 2056, 2058, 2060, 2062 and 2063), along with aplurality of IR sensors (e.g., five IR sensors 2064, 2066, 2068, 2070and 2071). Note that although only four laser optic assemblies andassociated IR sensors are shown in FIG. 42 for simplicity, five laseroptic assemblies and associated IR sensors are shown in FIG. 43. Thelaser optic assemblies are adapted to provide a laser beam to reseal theresealable stoppers on the vials after needle filling. Each of theplurality of laser optic assemblies is mounted at a respective locationadjacent to the guide 2010 for transmitting a respective laser beam ontothe resealable stopper of a respective vial 610 to heat seal the needleaperture in the resealable stopper. In addition, each laser opticassembly is aligned with a respective needle 2018 on the needle manifold2016 to seal the location of the resealable stopper pierced by therespective needle. Each of the laser optic assemblies 2056-2063 isconnected to a respective fiber optic cable that connects the respectiveoptic assembly to a respective laser source (not shown). As can be seen,providing multiple fiber optic assemblies makes it possible to resealmultiple vials concurrently. In this embodiment, each of the pluralityof IR sensor assemblies 2064-2071 is mounted adjacent to, and alignedwith a respective laser optic assembly and needle 2018 on the needlemanifold 2016. Preferably, the laser sources (not shown) are mountedoutside of the sterile enclosure of the needle filling machine withinwhich the module 2000 is mounted to enable repair and/or replacement ofthe laser sources without having to open the enclosure and/or otherwiserisk contamination of the sterile enclosure. The IR sensors 2064-2071detect the temperature of the needle penetration region of theresealable stopper achieved during laser resealing, and therefore can beused to determine whether the stopper was sufficiently reheated toachieve resealing. Each of the IR sensors 2064-2071 is connected to arespective IR sensor module (not shown). Providing multiple IR sensorsenables the sterile filling machine to sense the temperature of multiplevials concurrently, for example, as they are being resealed.

[0168] As described above, each laser source transmits a predeterminedwavelength of laser radiation at about 980 nm, and the predeterminedpower of each laser is preferably less than about 30 Watts, andpreferably less than or equal to about 10 Watts, or within the range ofabout 8 to about 10 Watts. In the illustrated embodiment, each lasersource is a semi-conductor diode laser that outputs at about 15 Watts,and is fiber-optically coupled through a fiber-optic cable to acollimating lens of the respective laser optic assembly. If desired, themodule 2000 can be enclosed, or partially enclosed within a tintedenclosure (not shown) including a plurality of tinted glass ortranslucent or transparent plastic panels that surround the laser opticassemblies on four sides to filter out potentially harmful radiationgenerated by the laser beams. In addition, capacitor sensors (not shown)may be provided downstream of the module 2000 in order to sense whethereach vial received the medicament or other substance to be containedtherein and to reject the vial if defective.

[0169] In the operation of the module 2000, the drive motor 2019 isrotatably driven in the direction of the arrow “b” to rotate the leadscrew 2015 and, in turn, transport the vials 610 along the guide 2012 inthe manner illustrated, for example, in FIG. 43. In the exemplary moduleof FIG. 43, the module includes five needles, five laser opticassemblies and five IR sensors, thus permitting the needle filling andlaser resealing of five vials at one time. Accordingly, the lead screw2015 is indexed five positions and then paused for a momentary dwell. Asmay be recognized by those or ordinary skill in the pertinent art basedon the teachings herein, the module 2000 may include any desired numberof needles, laser optic assemblies, and/or sensors. In addition, ifdesired, the lasers and sensors may be mounted within the moduledownstream of the needle manifold, to allow simultaneous filling andsealing of different vials, and thereby possibly increase the overallthroughput of the module. During the dwell, the needle manifold 2016 isdriven downward so as to drive the needles 2018 through the resealablestoppers on the vials beneath the needle manifold. Medicament or othersubstance is thereafter delivered by the pumps (not shown) through theneedles and into the interior chambers of the vials, and the manifold isthen driven up to thereby retract the needles 2018 from the stoppers. Inone embodiment, the needles are initially withdrawn at a relatively slowspeed to allow the vials to fill “bottom-up”; then, when the vials arefilled, the needles are withdrawn at a relatively faster speed toquickly remove the needles and decrease overall cycle time. As can beseen, the diabolo or spool-like shape of the vials facilitates theability to transport the vials in the conveying system, and further, thediabolo shape supports the vials and prevents axial movement of thevials during insertion and withdrawal of the needles during filling. Themid-portion of each vial is secured within the aperture 2014 of theguide 2010, the relatively larger diameter upper portion of each vialprevents axial downward movement of the vial upon inserting the needleinto the resealable stopper of the vial by engaging the upper surface ofthe guide, and the relatively larger diameter base portion of the vialprevents upward axial movement of the vial upon withdrawal of the needlefrom the resealable stopper by engaging the underside of the guide.

[0170] Also during the dwell, and following withdrawal of the needlesfrom the resealable stoppers, the laser optic assemblies 2056-2063deliver laser energy to the resealable stoppers on the vials to resealthe stoppers. As the resealable stoppers are heated by the laser energy,the IR sensors 2064-2071 detect the temperature of each stopper, so asto be able to determine whether each stopper was heated sufficient tocause resealing. After the dwell, the process is repeated, i.e., thelead screw indexes another five positions and then dwells again so thatthe next five vials can be filled and resealed.

[0171] As shown in FIG. 44, the module 2000 may be mounted in a sterileenclosure wherein the transport system includes an endless conveyor 2076and carriers 2078 mounted on the endless conveyor 2076 for transportingthe vials 610 through the module 2000. An infeed conveyor 2080 feeds thesealed, empty vials onto the carriers 2078 of the endless conveyor 2076.Then, the endless conveyor 2076 feeds the vials through the module 2000in the same manner, or in a manner similar to that described above.After the vials are filled and resealed in the module 2000, they aredispensed onto an outlet conveyor 2082. As may be recognized by those ofordinary skill in the pertinent art based on the teachings herein, theconveyers 2076, 2080 and 2082 and/or the components thereof may take theform of any of numerous different conveyors or conveyor components thatare currently, or later become known for performing the functions of oneor more of these conveyors or conveyor components.

[0172] As shown in FIG. 42, the module 2002 further includes an axiallyelongated port 2084 located on an opposite side of the needle manifold2016 relative to the laser optic assemblies and sensors for mountingtherein an e-beam unit 2086 that transmits an e-beam into theaxially-elongated chamber 2088 of the module and, in turn, sterilizesthe surfaces of the vial and the needle surfaces within the chamber. Thee-beam assembly, including the e-beam source, the chamber for containingthe e-beam, and the conveyor for conveying the vials through the e-beamchamber, may be the same as, or similar to that disclosed in co-pendingU.S. patent application Ser. No. 10/600,525, filed Jun. 19, 2003,entitled “STERILE FILLING MACHINE HAVING NEEDLE FILLING STATION WITHINE-BEAM CHAMBER”, and U.S. Provisional Patent Application Serial No.60/390,212, entitled “STERILE FILLING MACHINE HAVING NEEDLE FILLINGSTATION WITHIN E-BEAM CHAMBER”, filed Jun. 19, 2002, each of which ishereby expressly incorporated by reference as part of the presentdisclosure. As described in these co-pending patent applications, thee-beam unit may be any of numerous different types of e-beam units orsources that are currently, or later become known, for performing thefunction of the e-beam unit described herein.

[0173] E-beam radiation is a form of ionizing energy that is generallycharacterized by its low penetration and high dose rates. The electronsalter various chemical and molecular bonds upon contact with an exposedproduct, including the reproductive cells of microorganisms, andtherefore e-beam radiation is particularly suitable for sterilizingvials and other containers for medicaments or other sterile substances.An e-beam source produces an electron beam that is formed by aconcentrated, highly charged stream of electrons generated by theacceleration and conversion of electricity. Preferably, the electronbeam is focused onto a penetrable surface of each vial for piercing bythe respective needle. For example, in one embodiment, the electron beamis focused onto the upper surface of the resealable stopper to sterilizethe penetrable surface of the stopper prior to insertion of the fillingneedle therethrough. In addition, reflective surfaces may be mounted onopposite sides of the conveyor relative to each other to reflect thee-beam, and/or the reflected and scattered electrons, onto the sides ofthe vials to facilitate sterilization of these surfaces of the vial, ifnecessary. Alternatively, or in combination with such reflectivesurfaces, more than one e-beam source may be employed, wherein eache-beam source is focused onto a respective surface or surface portion ofthe vials or other containers to ensure sterilization of each surfacearea of interest. In some embodiments, the current, scan width, positionand energy of the e-beam, the speed of the transport system, and/or theorientation and position of any reflective surfaces, are selected toachieve at least about a 3 log reduction, and preferably about a 6 logreduction in bio-burden testing on the upper surface of the vial'sresealable stopper, i.e., the surface of the stopper defining thepenetrable region that is pierced by a respective filling needle to fillthe vial. In addition, as an added measure of caution, one or more ofthe foregoing variables also are preferably selected to achieve at leastabout a 3 log reduction on the sides of the vial, i.e., on the surfacesof the vial that are not pierced by the needle during filling. Inaddition, the e-beam may be directed onto the needles prior to entrythrough the resealable stoppers, or at least the portions of the needlesthat contact the stoppers, to further ensure sterilization of theneedles and vials. These specific levels of sterility are onlyexemplary, however, and the sterility levels may be set as desired orotherwise required to validate a particular product under, for example,United States FDA or applicable European standards, such as theapplicable Sterility Assurance Levels (“SAL”).

[0174] Turning to FIGS. 45-48, another vial embodying the presentinvention is indicated generally by the reference numeral 2200. The vial2200 is similar in many respects to the vial 900 described above withreference to FIGS. 29-31, and therefore like reference numerals precededby the numeral “22” instead of the numeral “9” are used to indicate likeelements. With reference to FIG. 45, a primary difference of the vial2200 in comparison to the vial 900 described above is that thefrusto-conical or innermost edge 2265 of the locking ring 2250 is spacedrelatively inwardly to, in turn, permit a filling needle 2018 to piercethe resealable stopper 2230 at an acute angle “D” relative to the axisof the vial and in a peripheral portion of the penetrable region 2231 ofthe stopper. One advantage of this configuration is that, as shown inFIG. 47, the penetrated and laser (or otherwise thermally) resealedportion 2231 of the stopper is located on a marginal or peripheralportion of the region 2231 of the stopper, and thus can be concealedunder an inner edge 2233 of the tamper-resistant cover 2240 when thefrangible portion 2260 of the tamper-resistant cover is removed in use,as described further below.

[0175] As can be seen, the locking ring 2250 defines a peripheral flangeforming the neck 2216 and further defines on its interior edge anannular recess 2268 for receiving therein an annular protuberance 2266formed on the tamper-resistant cover 2250. The interior edge of theannular flange 2216 leading into the recess 2268 may define a chamferedsurface, and the leading edge of the annular protuberance 2266 of thecover also may be chamfered to allow the protuberance to be snappedinto, or otherwise fixedly received within the recess, but to preventremoval of the cover therefrom. Similarly, the locking ring 2250 defineson its inner diameter an annular protuberance 2221 that is snapped into,or otherwise fixedly received within a corresponding annular recess 2223formed on the exterior of the vial body 2210 to fixedly secure thelocking ring 2250 to the vial body. In this embodiment, the base 2214 ofthe vial body 2210 is formed integral with the remainder of the vialbody in order to reduce the number of parts; however, if desired, thebase 2214 can be made as a separate part that is snap-fit or otherwiseattached to the vial body.

[0176] As shown in FIGS. 47 and 48, the tamper-resistant cover 2240defines a centrally-located frangible portion 2260, and an inwardlydepending annular protuberance 2263 that engages the exposed surface ofthe stopper 2230 and, if desired, may form a hermetic or gas-tight sealtherebetween. As shown in FIGS. 47 and 48, a plurality of frangibleconnections 2262 are angularly spaced relative to each other and extendbetween the frangible portion 2260 and a substantially dome-shaped coverbody 2241 to allow removal of the frangible portion and access to theunderlying stopper 2230. The frangible portion 2260 of the cover ispressed downwardly by, for example, a user's finger, to slightly depressthe underlying stopper material and, in turn, break the frangibleconnections 2262. Once removed, the frangible portion 2260 cannot bereconnected to thereby provide a tamper-proof feature. Thetamper-resistant cover 2240 further includes a second downwardlydepending protuberance 2235 located adjacent to the first protuberance2263 and in engagement with the exposed stopper to form a hermetic orgas-tight seal therebetween. If desired, the first and second annularprotuberances 2263 and 2235, respectively, may be formed contiguous witheach other to, in turn, form a gas-tight or hermetic seal therebetween,and thereby increase the MVT barrier of the vial in the directionthrough the stopper.

[0177] As indicated in FIG. 45, the vial 2200 may be filled in, forexample, a needle filling and laser resealing module as described above.However, one difference enabled by the vial 2200 is that the needle 2018is inserted into the penetrable region 2231 of the resealable stopper2230 at an acute angle “D” relative to the axis of the vial, and in amarginal or outer peripheral portion of the penetrable region adjacentto the inner edge 2265 of the locking ring 2250. As can be seen incomparison to the locking ring 950 described above in connection withFIG. 29, the inner edge 2265 of the locking ring 2250 is spaced radiallyoutwardly to, in turn, expose the marginal portion of the penetrableregion 2231 of the stopper and permit same to be penetrated by theneedle 2018 at the acute angle “D”. One advantage of penetrating thestopper 2230 with the needle 2018 at the acute angle D, is that thefluid injected by the needle is directed onto the side wall of the vialbody 2210 substantially at the acute angle, as indicated by the arrow“E” in FIG. 45, and thus facilitates creating a laminar flow, orsubstantially laminar flow of fluid into the vial. This type of flowfacilitates in preventing the formation of bubbles or like turbulenteffects upon filling the vial with fluid, and thus permits the vials tobe filled more quickly and/or otherwise in a more desirable manner. Asmay be recognized by those of ordinary skill in the pertinent art basedon the teachings herein, the acute angle “D” may be created by orientingthe needles on the needle manifold at an acute angle relative to theaxis of the vial, or by orienting the axes of the vials in the fillingstation at an acute angle relative to the axes of the needles, or acombination of both. In the illustrated embodiment, the angle “D” iswithin the range of about 30° to about 45°; however, these angles areonly exemplary, and may be changed as desired to obtain the desired flowand/or filling characteristics, or otherwise as desired to meet therequirements of a particular application.

[0178] Another advantage of this embodiment of the present invention isthat the penetrated/resealed portion of the stopper may be visuallyconcealed from the end user throughout the use of the vial. As showntypically in FIG. 47, the needle hole, and thus the resealed portion2231 of the stopper, is concealed under the inner edge portion 2233 ofthe tamper-resistant cover 2240. Accordingly, upon removing thefrangible portion 2260 of the tamper-resistant cover 2240 to access witha syringe the contents of the vial, the underlying and visually exposedportion of the stopper 2230 does not include the resealed portion 2231,and thus may be considered more aesthetically desirable or pleasing thanhaving the resealed portion visually exposed.

[0179] As may be recognized by those skilled in the pertinent art basedon the teachings herein, numerous changes and modifications may be madeto the above-described and other embodiments of the present applicationwithout departing from the inventive aspects disclosed herein. Forexample,.the resealable portion may be integrally molded with a basesuch as by insert molding, the resealable portion may be fused orotherwise melted to a base, or the resealable portion may besequentially molded to a base. Alternatively, the resealable stopper maybe formed of only one material, i.e., the resealable portion with theinfusible base or other infusible layer, may be formed with multiplelayers, wherein some or all of the layers are thermally resealable.Thus, the resealable stopper may be made of any of numerous differentmaterials which are currently known, or later become known forperforming the functions of the resealable portion or stopper describedherein, such as any of numerous different thermoplastic and/orelastomeric materials. In addition, the vials may be made of any ofnumerous different materials that are currently or later become knownfor forming vials, such as medicament vials, including any of numerousdifferent types of glass or plastic, or combinations of glass andplastic. For example, the vial body can be formed of glass, and thebase, locking ring and/or tamper-resistant cover can be formed ofplastic, and can be joined to the body or to each other in accordancewith any of numerous different joining mechanisms that are currently, orlater become known, such as by over-molding, mechanical snap-fit orother interlocking engagements, by adhesively joining glass to plastic,or by ultrasonically welding or otherwise welding plastic to plastic. Inaddition, the needles used to fill the vials may take the form of any ofthe needles disclosed in British patent application no. GB 0308705.2,filed Apr. 28, 2003, entitled “Novel Device”, the vial closure may takeany of the forms of the closures disclosed in British patent applicationno. GB0304268.6, filed Feb. 26, 2003, entitled “Novel Device”, theconveyor system and/or the components thereof may take any of the formsas shown in British patent application no. GB0221510.1, filed Sep. 17,2002, entitled “Novel Device”, and the needle filling and/or processingstations may take any of the forms shown in British patent applicationno. GB0221511.9, filed Sep. 17, 2002, entitled “Novel Device”, each ofwhich is hereby expressly incorporated by reference in its entirety aspart of the present disclosure. Accordingly, this detailed descriptionof the preferred embodiments is to be taken in an illustrative, asopposed to a limiting sense.

What is claimed is:
 1. A vial assembly for storing a substance, comprising: a body defining an opening, a chamber in fluid communication with the opening for receiving therein the substance, a base, a mid-portion, and an upper portion axially spaced from the base on an opposite side of the mid-portion relative to the base, wherein each of the base and upper portion define a laterally-extending dimension greater than a maximum laterally-extending dimension of the mid-portion; and a stopper received within the opening and penetrable by a needle or like member for at least one of introducing the substance into, and withdrawing the substance from, the chamber.
 2. A vial assembly as recited in claim 1, wherein each of the base, mid-portion and upper portion are approximately circular in cross section, and a maximum diameter of each of the base and upper portion is greater than a maximum diameter of the mid-portion.
 3. A vial assembly as recited in claim 2, wherein the base, mid-portion and upper portion are substantially spool shaped.
 4. A vial assembly as defined in claim 1, further comprising: a tamper-resistant, substantially ring-shaped portion fixedly secured to the body and extending at least partially over the stopper for preventing unnoticeable removal of the stopper.
 5. A vial assembly as defined in claim 4, wherein the tamper-resistant portion is thermally fused to the body.
 6. A vial assembly as recited in claim 5, wherein the tamper-resistant portion is over-molded to the stopper and body.
 7. A vial assembly as recited in claim 5, wherein the tamper-resistant portion is formed integral with the stopper, and the integral stopper and tamper-resistant portion is over-molded to the body.
 8. A vial assembly as recited in claim 4, wherein the tamper-resistant portion defines a thermally-fused region forming a hermetic seal between the tamper-resistant portion and at least one of the body and stopper.
 9. A vial assembly as recited in claim 1, further comprising a tamper-resistant portion fixedly secured to the vial body and completely overlying the stopper, wherein the stopper and tamper-resistant portion are penetrable by a needle for introducing a substance into the interior chamber of the vial, and the tamper-resistant portion is fusible in response to the application of thermal energy thereto for hermetically sealing any hole created in the tamper-resistant portion by the needle upon removal of the needle.
 10. A vial assembly as recited in claim 4, wherein the stopper has an annular groove defined in an outer periphery thereof such that an annular recess is formed between the stopper and the body, and the tamper-resistant portion is at least partially formed in the annular recess.
 11. A vial assembly as recited in claim 1, wherein the stopper includes a heat resealable portion overlying a substantially infusible portion.
 12. A vial assembly as recited in claim 1, wherein the stopper is a thermoplastic stopper defining a needle penetration region that is pierceable with a needle to form a needle aperture therethrough, and is heat resealable to hermetically seal the needle aperture by applying laser radiation at a predetermined wavelength and power thereto, wherein the stopper comprises a thermoplastic body defining (i) a predetermined wall thickness in an axial direction thereof, (ii) a predetermined color and opacity that substantially absorbs the laser radiation at the predetermined wavelength and substantially prevents the passage of the radiation through the predetermined wall thickness thereof, and (iii) a predetermined color and opacity that causes the laser radiation at the predetermined wavelength and power to hermetically seal a needle aperture formed in the needle penetration region thereof in a predetermined time period of less than approximately 2 seconds and substantially without burning the needle penetration region.
 13. A vial assembly as recited in claim 12, wherein the needle penetration region of the stopper is formed of a thermoplastic consisting essentially of a styrene block copolymer and an olefin.
 14. A vial assembly as recited in claim 12, wherein the ratio of the styrene block copolymer to the olefin are within the range of about 50:50 by weight to about 90:5 by weight.
 15. A vial assembly as recited in claim 12, wherein the predetermined wavelength is approximately 980 nm.
 16. A vial assembly as recited in claim 12, wherein the predetermined power is less than approximately 30 Watts.
 17. A vial assembly as recited in claim 16, wherein the predetermined power is less than or equal to about 10 Watts.
 18. A vial assembly as recited in claim 12, wherein the predetermined color is gray.
 19. A vial assembly as recited in claim 12, wherein the predetermined time period is less than about 1.5 seconds.
 20. A vial assembly as recited in claim 12, wherein the predetermined wavelength is about 980 nm, the predetermined power is within the range of about 8 to 10 Watts, the predetermined color is gray, and the predetermined opacity is defined by a dark gray colorant additive within the range of about 0.3% to about 0.6% by weight.
 21. A vial assembly as recited in claim 1, in combination with a vial support including a vial mounting surface engageable with the mid-portion of the vial, an upper surface located on one side of the mounting surface, and a lower surface located on another side of the mounting surface, wherein the upper portion of the vial is engageable with the upper surface of the vial support for substantially preventing axial movement of the vial relative thereto, and the base of the vial is engageable with the lower surface of the vial support for substantially prevent axial movement of the vial relative thereto.
 22. An assembly as recited in claim 21, further comprising a filling module comprising a needle manifold including a plurality of needles spaced relative to each other and movable relative to the vial support for penetrating a plurality of vials mounted on the support within the module, filling the vials through the needles, and withdrawing the needles from the filled vials.
 23. An assembly as recited in claim 22, wherein the module further comprises a plurality of laser optic assemblies, wherein each laser optic assembly is mounted adjacent to a respective needle, is connectable to a source of laser radiation, and is focused substantially on the penetration spot on a stopper of the respective needle for applying laser radiation thereto and resealing same.
 24. An assembly as recited in claim 23, wherein the module further comprises a plurality of optical sensors, wherein each sensor is mounted adjacent to a respective laser optic and focused substantially on the laser resealed region of a stopper of the respective laser optic assembly, and generates signals indicative of the temperature of same.
 25. An assembly as recited in claim 23, further comprising an e-beam port, a chamber receiving at least the portions of the needles that penetrate the stoppers and at least the surfaces of the stoppers that are penetrated by the needles, and an e-beam unit coupled to the e-beam port, wherein the e-beam unit transmits an e-beam into the chamber and onto surfaces of the needles and stoppers received within the chamber for sterilizing same.
 26. A vial assembly as recited in claim 1, in combination with at least one filling needle movable relative to the vial assembly for penetrating the stopper, filling the chamber of the vial assembly through the needle, and withdrawing the needle from the filled vial assembly, and wherein at least one of the needle and an axis of the vial is oriented at an acute angle relative to the other.
 27. A vial assembly as recited in claim 1, further comprising: a tamper-resistant, substantially ring-shaped portion fixedly secured to the body, extending at least partially over the stopper for preventing unnoticeable removal of the stopper, and exposing a central portion of the stopper for penetrating same with a needle for removing substance from the chamber of the body; and a tamper-resistant cover overlying the ring-shaped portion and including a removable portion overlying an exposed central portion of the stopper, and a non-removable portion spaced laterally outwardly relative to the removable portion, wherein the removable portion is removable from the tamper-resistant cover to expose a portion of the stopper for penetrating same with a needle and removing substance from the chamber of the body therethrough, and the stopper defines a thermally resealed portion spaced laterally outwardly relative to the exposable portion of the stopper and underlying the non-removable portion of the tamper-resistant cover for substantially visually concealing same from a user.
 28. A vial assembly for storing a substance, comprising: a body defining an opening, a chamber in fluid communication with the opening for receiving therein the substance, a base, a mid-portion, and an upper portion axially spaced from the base on an opposite side of the mid-portion relative to the base, wherein each of the base and upper portion define a laterally-extending dimension greater than a maximum laterally-extending dimension of the mid-portion; and first means received within the opening for sealing the opening and being penetrable by a needle for at least one of introducing the substance into, and withdrawing the substance from, the chamber.
 29. A vial assembly as defined in claim 28, further comprising: second means fixedly secured to the first means and extending between the body and fist means for preventing unnoticeable removal of the first means.
 30. A vial assembly as recited in claim 28, wherein the first means is defined by a stopper.
 31. A vial assembly as recited in claim 30, wherein the stopper is heat-resealable.
 32. A vial assembly as recited in claim 29, wherein the second means is thermally fused to at least one of the body and stopper.
 33. A vial assembly as recited in claim 29, wherein the second means is a tamper-resistant ring.
 34. A vial assembly as recited in claim 32, wherein the second means is over-molded to at least one of the first means and vial body.
 35. A vial assembly as recited in claim 32, wherein the second means is formed integral with the first means and the integral first and second means is over-molded to the body.
 36. A vial assembly as recited in claim 28,wherein each of the base, mid-portion and upper portion are approximately circular in cross section, and a maximum diameter of each of the base and upper portion is greater than a maximum diameter of the mid-portion.
 37. A vial assembly as recited in claim 36, wherein the base, mid-portion and upper portion define an approximate diabolo shape.
 38. A vial assembly as recited in claim 28, wherein the first means is a thermoplastic stopper defining a needle penetration region that is pierceable with a needle to form a needle aperture therethrough, and is heat resealable to hermetically seal the needle aperture by applying laser radiation at a predetermined wavelength and power thereto, wherein the stopper comprises (i) a thermoplastic body defining a predetermined wall thickness in an axial direction thereof, (ii) third means for substantially absorbing the laser radiation at the predetermined wavelength and substantially preventing the passage of the radiation through the predetermined wall thickness thereof, and (ii) fourth means for causing the laser radiation at the predetermined wavelength and power to hermetically seal a needle aperture formed in the needle penetration region thereof in a predetermined time period of less than approximately 2 seconds and substantially without burning the needle penetration region.
 39. A vial assembly as recited in claim 38, wherein the third means is defined by a predetermined color and opacity that substantially absorbs the laser radiation at the predetermined wavelength and substantially prevents the passage of the radiation through the predetermined wall thickness thereof.
 40. A vial assembly as recited in claim 38, wherein the fourth means is defined by a predetermined color and opacity that causes the laser radiation at the predetermined wavelength and power to hermetically seal a needle aperture formed in the needle penetration region thereof in a predetermined time period of less than approximately 2 seconds and substantially without burning the needle penetration region.
 41. A vial assembly as recited in claim 28, wherein the first means is defined by a stopper including a heat resealable portion overlying a substantially infusible portion.
 42. A method comprising the following steps: providing a vial including a body defining an opening, a chamber in fluid communication with the opening for receiving therein a predetermined substance, a base, a mid-portion, and an upper portion axially spaced from the base on an opposite side of the mid-portion relative to the base, wherein each of the base and upper portion define a laterally-extending dimension greater than a maximum laterally-extending dimension of the mid-portion, and a heat-resealable stopper fusible in response to the application of thermal energy thereto; prior to filling the vial with substance, assembling the stopper and vial and forming a substantially gas-tight seal between the stopper and vial; sterilizing the empty assembled stopper and vial; supporting the a vial with a vial support including mounting surface in engagement with the mid-portion of the vial, an upper surface located on one side of the mounting surface, and a lower surface located on another side of the mounting surface; penetrating the stopper with a needle coupled in fluid communication with a source of predetermined substance; introducing the predetermined substance through the needle and into the interior of the vial; withdrawing the needle from the stopper; and applying sufficient thermal energy to the penetrated region of the stopper to fuse the penetrated region and form a substantially gas-tight seal between the penetrated region and the interior of the vial.
 43. A method as recited in claim 42, further comprising the steps of substantially preventing axial movement of the vial during needle penetration of the vial by engaging at least one of the upper surface of the vial support and the upper portion of the vial with the other.
 44. A method as recited in claim 42, wherein the step of sterilizing the empty vial and stopper assembly includes at least one of applying gamma radiation, e-beam radiation or laser radiation thereto.
 45. A method as recited in claim 42, wherein the step of assembling the stopper to the vial includes fusing a tamper-resistant portion between the stopper and vial.
 46. A method as recited in claim 45, wherein the step of assembling the stopper to the vial includes over-molding the tamper-resistant portion to the stopper and vial.
 47. A method as recited in claim 45, comprising the step of forming the tamper-resistant portion integral with the stopper and over-molding the integral stopper and tamper-resistant portion to the vial.
 48. A method as recited in claim 42, comprising the steps of assembling the stopper and vial robotically and over-molding a tamper-resistant portion between the stopper and vial
 49. A method as recited in claim 48, wherein the assembly of the vials and stoppers occurs prior to installing the vial/stopper assembly in the over-molding apparatus.
 50. A method as recited in claim 48, wherein the vials and stoppers are assembled in an over-molding apparatus so that the step of over-molding the tamper-resistant portions can be achieved without further transportation of the vial/stopper assembly.
 51. A method as recited in claim 42, further comprising the step of orienting at least one of an axis of the vial and an axis of the needle at an acute angle relative to the other defining a needle penetration axis through the stopper oriented at an acute angle relative to the axis of the vial.
 52. A method as recited in claim 42, further comprising the step of introducing the substance through the needle at said acute angle and against a lateral wall of the body to facilitate substantially laminar flow of the substance into the vial. 